Brain-specific nutrients: a memory cure? Part 1

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PART 1

 

Nutrition

Vol: 19 Issue: 11-12, November - December, 2003 pp: 994-996

 

Article Full Text

 

“Brain-specific” nutrients: a memory cure?*1

Mark A. McDaniela, , , , Steven F. Maierb, Gilles O. Einsteinc

a. Department of Psychology, University of New Mexico, Albuquerque, New

Mexico , USA

b. Department of Psychology, University of Colorado, Boulder, Colorado , USA

c. Department of Psychology, Furman University, Greenville, South Carolina

, USA

 

 

Article Outline:

1. Objective

2. Results

3. Conclusions

1. Introduction

2. Nootropics, the aging brain, and neural bases of learning and memory

 

a. The aging brain

b. The neural basis of learning and memory

3. Phosphatidylserine

 

a. Mechanisms and animal studies

b. Controlled human studies

i. Effects on patients with moderate cognitive impairments

ii. Effects on normal older adults

iii. Safety

c. Summary

4. Choline

 

a. Mechanisms and animal studies

b. Controlled human studies

i. Phosphatidylcholine

ii. Citicoline

iii. Safety

c. Summary

5. Piracetam

 

a. Mechanisms and animal studies

b. Controlled human studies

i. Effects on patients with probable Alzheimer´s disease

ii. Effects in other populations

iii. Safety

c. Summary

6. Vinpocetine

 

a. Mechanisms and animal studies

b. Controlled human studies

i. Effects on patients with cognitive impairments

ii. Effects on normal younger adults

iii. Safety

c. Summary

7. Acetyl-l-carnitine

 

a. Mechanisms and animal studies

b. Controlled human studies

i. Effects on patients with probable Alzheimer´s disease

ii. Effects in other populations

iii. Safety

c. Summary

8. Antioxidants

 

a. Mechanisms and animal studies

b. Controlled human studies

i. Effects on normal younger adults

ii. Effects on patients with brain pathology

iii. Safety

c. Summary

9. Future work and more fine-grained analyses of memory

10. Ginkgo and ginseng

 

a. Estrogen and related hormones

11. Summary and concluding remarks

Acknowledgements

References

 

Abstract

1. Objective

We review the experimental evaluations of several widely marketed

nonprescription compounds claimed to be memory enhancers and treatments for

age-related memory decline. We generally limit our review to double-blind

placebo-controlled studies. The compounds examined are phosphatidylserine

(PS), phosphatidylcholine (PC), citicoline, piracetam, vinpocetine,

acetyl-L-carnitine (ALC), and antioxidants (particularly vitamin E).

 

2. Results

In animals, PS has been shown to attenuate many neuronal effects of aging,

and to restore normal memory on a variety of tasks. Preliminary findings

with humans, though, are limited. For older adults with probable

Alzheimer´s disease, a single study failed to demonstrate positive effects

of PS on memory performance. For older adults with moderate cognitive

impairment, PS has produced consistently modest increases in recall of word

lists. Positive effects have not been as consistently reported for other

memory tests. There is one report of consistent benefits across a number of

memory tests for a subset of normal adults who performed more poorly than

their peers at baseline.

 

The choline compounds PC and citicoline are thought to promote synthesis

and transmission of neurotransmitters important to memory. PC has not

proven effective for improving memory in patients with probable Alzheimer´s

disease. The issue remains open for older adults without serious

degenerative neural disease. Research on citicoline is practically

nonexistent, but one study reported a robust improvement in story recall

for a small sample of normally aging older adults who scored lower than

their peers in baseline testing.

 

Animal studies suggest that piracetam may improve neuronal efficiency,

facilitate activity in neurotransmitter systems, and combat the age-related

decrease in receptors on the neuronal membrane. However, for patients with

probable Alzheimer´s disease, as well as for adults with age-associated

memory impairment, there is no clear-cut support for a mnemonic benefit of

piracetam.

 

Vinpocetine increases blood circulation and metabolism in the brain. Animal

studies have shown that vinpocetine can reduce the loss of neurons due to

decreased blood flow. In three studies of older adults with memory problems

associated with poor brain circulation or dementia-related disease,

vinpocetine produced significantly more improvement than a placebo in

performance on global cognitive tests reflecting attention, concentration,

and memory. Effects on episodic memory per se have been tested minimally,

if at all.

 

ALC participates in cellular energy production, a process especially

important in neurons, and in removal of toxic accumulation of fatty acids.

Animal studies show that ALC reverses the age-related decline in the number

of neuron membrane receptors. Studies of patients with probable Alzheimer´s

disease have reported nominal advantages over a range of memory tests for

ALC-treated patients relative to placebo groups. Significant differences

have been reported rarely, however. Whether ALC would have mnemonic

benefits for aging adults without brain disease is untested as far as we know.

 

Antioxidants help neutralize tissue-damaging free radicals, which become

more prevalent as organisms age. It is hypothesized that increasing

antioxidant levels in the organism might retard or reverse the damaging

effects of free radicals on neurons. Thus far, however, studies have found

that vitamin E does not significantly slow down memory decline for

Alzheimer´s patients and does not produce significant memory benefits among

early Parkinson´s patients. Neither did a combination of vitamins E and C

significantly improve college students´ performance on several cognitive tasks.

 

3. Conclusions

In sum, for most of the “brain-specific” nutrients we review, some mildly

suggestive effects have been found in preliminary controlled studies using

standard psychometric memory assessments or more general tests designed to

reveal cognitive impairment. We suggest that future evaluations of the

possible memory benefits of these supplements might fruitfully focus on

memory processes rather than on memory tests per se.

 

1. Introduction

Memory decline with age has been well documented in the experimental

literature for some time.[ 1 ] As Figure 1 shows, in humans this decline

may start as early as 30 y of age, with significant decline evidenced by

middle age, at least for paired-associate memory. These experimental

findings are echoed in people´s personal observations that as they age,

their memory seems to get worse. In a sample of 280 people of varying ages

whom we queried, we found a threefold increase from the decade of the 30s

to the decade of the 40s in the percentage of people reporting that they

perceived having some problems with memory. Almost a third of the people in

their 40s felt that these problems might be suggestive of Alzheimer´s

disease.[ 2 ] Thus, as people age, they appear to have a strong tendency to

develop the impression that their memory is declining, an impression that

dovetails with the experimental literature.

 

 

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FIG. 1: Paired-associate learning at various ages. The scores are expressed

as a percentage of the maximum score across all ages. Each line shows the

results of a separate experiment (identified by the number next to the

line). Reprinted from Salthouse[ 117 ] (p. 126) by permission of the author.

 

 

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In view of these observations, it is natural that the public has an

interest in supplements that are touted to improve memory, forestall memory

decline, or help remedy age-related declines in memory. These supplements

are easily available and are widespread, dispensed either individually or

in combinations as “memory cocktails.” These products are frequently

advertised on the radio, in magazines directed at the aging population, and

in publications about natural remedies to physical and psychological

ailments. It is not surprising, then, that when memory psychologists are

engaged in social conversations about memory, they are often asked, “Are

there supplements I can take that are supposed to help memory?” and “Do

these supplements really work?” These questions are reasonable, and the

answers hold importance for individuals who are experiencing age-related

memory declines or age-related neural pathology, or who have friends and

relatives with such concerns.

 

Unfortunately, these questions cannot be answered by appealing to the

mainstream experimental psychology journals, as the issue has not

penetrated these journals. Neither can the questions be answered

confidently by examining trade books on “brain fitness,” “memory cures,”

and so on. In the case of such non-peer-reviewed publications, the cautious

reader has reason to question the nature of the database examined, the

extent to which the scientific database has been probed, and the leniency

with which the data have been interpreted. Further, marketing these

products as “memory enhancers” and “brain boosters,” without any proof of

efficacy, is legal as long as there are no claims that they are effective

in treating or curing disease or illness.

 

Accordingly, the purpose of this review is to identify supplements that

have enjoyed reputations as memory enhancers, to consider the possible

neurological or physiological mechanisms by which they might affect memory,

and to report on the existing behavioral evaluations of their efficacy. At

the outset, we were unsure whether such scientific studies existed, and

were somewhat skeptical that the claims in the popular press about the

memory benefits of these supplements would find any support in

well-conducted research. To foreshadow our conclusions, we were somewhat

surprised by the number of supplements (in addition to ginkgo) that are

hypothesized to increase memory functioning and also by the research

findings, which do not justify outright dismissal of some of these supplements.

 

2. Nootropics, the aging brain, and neural bases of learning and memory

The term nootropics (from the Greek “noos” and “tropein,” meaning “mind”

and “toward,” respectively) was originally coined to describe the

pharmacology of a particular drug, piracetam,[ 3 ] and has now been adopted

more generally as a label for the class of agents that 1) improve cognitive

functions like memory and learning; 2) provide neuroprotective effects from

various insults; 3) do not possess properties of classical excitants,

tranquilizers, and antipsychotics; and 4) have very limited or no side

effects.[ 4 ] In this article, we review the existing experimental

evaluations of several widely marketed nonprescription agents claimed to

have nootropic effects. These drugs (mostly nonprescription) and nutrients

are featured in the popular press as memory- or cognitive-enhancing

supplements, and are recommended as part of treatment regimens at some

aging clinics. They include Ginkgo biloba. phosphatidylserine (PS),

vinpocetine, acetyl-L-carnitine (ALC), piracetam, choline-related nutrients

thought to be involved in producing acetylcholine (ACh), and antioxidant

agents like vitamin E. These are often combined into memory-cocktail

supplements and sold commercially. For example, the first four nutrients

listed have recently been combined into a single cocktail supplement and

sold as Memory 2000 (produced by Natural Balance).

 

2.a. The aging brain

The presumed neural benefits of these nootropic agents may articulate well

with the neural declines associated with normal aging and with degenerative

neural pathologies commonly seen in older adults. The growing evidence

suggests at least three prominent global changes in the brain that occur

with age. First, the neurons show multiple changes, and neuronal changes

are a more decisive hallmark of age than widespread death of neurons.[ 5 ]

Briefly, the aging-related neuronal changes include accumulation of

nonessential substances (e.g., yellowish brown lipid lipofuscin—“wear and

tear” pigment), loss of essential myelin (fatty material around axons; the

axon conducts an electrical signal away from the neuron body, and myelin

promotes speedy and reliable propagation of the signal), and general

shrinkage. With regard to age-related changes in memory and cognitive

functioning, it is perhaps significant that lipid lipofuscin accumulates

prominently in cortical neurons,[ 5 ] and myelin loss is most notable in

the association and limbic cortices (specific areas of the cerebral

cortex).[ 6 ]

 

Second, the connections between neurons, not just the neurons themselves,

change with age. There is a reduction in the branching of dendrites (fibers

on which axons of other neurons terminate) and a decline in the number of

properly functioning connections between neurons.[ 5 ] Aging may depress

the availability of neurotransmitters such as ACh, and ACh seems to be

heavily involved in neuron networks associated with memory. Third, with age

the cerebrovascular system shows numerous structural changes, diminishing

cerebral blood flow, and declining cerebral blood volume. With extreme

shortage or suppression of blood flow, a condition called ischemia exists.

 

As we discuss in the individual sections dedicated to the various nootropic

agents, and as we summarize in - Table: [ 1], some nootropics may help stem

age-related changes in neurons by providing the essential substances for

cell membrane health (e.g., PS, citicoline) or by protecting neurons

against toxic effects produced by oxidative processes (e.g., antioxidants)

and other sources (e.g., ALC, piracetam). Some nootropics may augment

neuronal connections by promoting branching of dendritic spines (PS),

maintaining neuron receptors (PS, ALC, piracetam), or stimulating the

production or release of ACh (cholines, ALC, piracetam). Other agents may

function by increasing blood flow (vinpocetine).

 

 

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Table I: THEORETICAL MECHANISMS OF NUTRIENTS CLAIMED TO BE MEMORY ENHANCERS

 

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2.b. The neural basis of learning and memory

Before proceeding, it is necessary to preview how neuronal functions and

connections underlie learning and memory. Because learning and memory

involve the retention of information over long periods of time, they must

be mediated by relatively permanent changes in the networks of neurons that

represent the information. Unraveling the mystery of how this occurs has

been a fascinating success story of modern science, and the broad outline

is as follows. It all begins with the release of a neurotransmitter, the

chemical messenger between neurons, from terminals in the axon of a neuron.

The neurotransmitter molecules then bind to receptors on the membrane of

the dendrites of nearby neurons, thereby initiating a complex cascade of

events within those neurons that lead to the permanent changes that are memory.

 

The binding of a neurotransmitter to one type of receptor (ionotropic

receptors) allows ions of various kinds to rapidly cross the cell membrane

into the neuron. This passage of ions changes the electrical potential

between the inside and outside of the neuron and causes the neuron to

“fire” an electrical signal. However, this occurs within milliseconds and

does not produce a long-term change in the neuron, and thus cannot be the

basis of memory.

 

But there is a second type of receptor. The binding of a neurotransmitter

to this type of receptor (metabotropic receptors) induces the production of

what are called second-messenger molecules (the neurotransmitter is the

first messenger) within the neuron. These second messengers travel within

the neuron, initiating a large number of different biological reactions and

controlling the functioning of the neuron. The reaction of most importance

for memory is the activation of a number of different enzymes called

kinases. The functioning of any cell is determined by the proteins that are

produced in the cell and their activity, and kinases selectively alter the

activity of proteins. Kinases can remain active for hours once activated,

and so have time to produce many prolonged alterations within the neuron.

In addition, some kinases can enter the nucleus and initiate the activation

of specific genes, thereby leading to the production of novel proteins and

thus an altered neuron—a memory. Some of these new proteins then produce

physical growth of the neural fibers that directly interact with other

neurons. For example, new spines may form on the dendrites of the neuron,

thus strengthening its connection to the neuron that began it all by

releasing the neurotransmitter. These new physical structures can be

relatively permanent and form the physical basis for a stable memory.

Figure 2 provides an illustrative schematic of the neural processes just

discussed.

 

 

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FIG. 2: Illustration of how two neurons communicate. In the neuron that

sends the “message” (i.e., the presynaptic neuron), neurotransmitters (the

chemical messengers that communicate between neurons) are synthesized and

packaged into vesicles. These vesicles are located at terminals at the ends

of the neuron´s axon. If the neuron becomes sufficiently depolarized, the

transmitter molecules are extruded across the cell membrane and enter the

space between this neuron and neurons nearby (the synaptic cleft). The

transmitter molecules then bind to receptors on the surface of these

postsynaptic neurons (dendrites). There are two main types of receptors:

ion-channel and G-protein–coupled receptors ®. The binding of a

transmitter to an ion-channel receptor leads the channel to open, allowing

specific ions to enter the neuron across the membrane. This is the way in

which rapid changes in the postsynaptic neuron are produced. The binding of

a transmitter to the surface of a G-protein–coupled receptor leads to

alterations in the state of proteins (G) that are coupled to the receptor.

This alteration then leads to the production of second-messenger molecules,

which can exert both immediate and more prolonged effects on the neuron.

For example, as illustrated, these messengers can lead to the activation of

substances called protein kinases. These protein kinases can, in turn,

enter the nucleus of the neuron and act on transcription factors that

regulate the transcription of DNA into RNA. Thus, activation of these

receptors can alter the genes that are expressed by the postsynaptic

neuron, thereby producing the long-term changes that are involved in memory.

 

 

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The compromised communication between neurons that is associated with aging

and brain disease may be due to a decrease in the production of

neurotransmitters or a deficit in any of the processes involved in the

complex cascade of biological events that intervene between the binding of

a neurotransmitter to a receptor and long-term alterations in the

functional state of the neuron. More specifically, there are likely

declines in aspects of the processes within the neuron, such as the

activity of kinases, that lead to the long-term, stable changes that form

the basis of memory. The theory is that memory decline might be avoided by

using nootropic-like agents to slow down neuron and brain-tissue loss and

loss of function so as to restore depleted memory-related neural processes.

 

Because the mnemonic effects of these agents seem most likely to emerge in

older populations that are at risk for neural impairment, and because the

need for nootropic agents is pressing for aging individuals, especially

those with dementias, the scientific evaluation of such agents has been

almost exclusively conducted with older adults having demonstrated memory

impairment. Ideally, a complete understanding and evaluation of the effects

of supplements on memory would specify the particular neural or metabolic

influence of each supplement; identify age-related changes in neural

functioning; delineate the possible effects of age and supplements on

particular neuropsychological systems; and link these effects to particular

kinds of memory functioning. Unfortunately, none of these issues is well

understood, and the experimental human studies have not been guided by this

kind of rich theoretical orientation. In our review of the experimental

findings, we have attempted to synthesize as much information pertaining to

these fundamental issues as the literature allows, and we hope that in so

doing we have provided a solid foundation for further systematic research

on nootropic supplements.

 

We generally limit our review to double-blind, placebo-controlled studies,

as placebo and expectation effects can seriously compromise the

interpretation of studies without these experimental safeguards.[ 7 ] Also,

because a recent report by Gold et al.[ 8 ] focuses on Ginkgo biloba, we

limit discussion of ginkgo to one recent experimental finding. Our primary

goal is to examine the various other supplements claimed to have memory

benefits. - Table: [ 2]summarizes the results of the human studies we

report in the sections that follow.

 

 

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Table II: SUMMARY OF HUMAN EXPERIMENTAL FINDINGS

 

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3. Phosphatidylserine

In recent years, PS has created excitement as a potential “brain-specific”

nutrient to help older adults improve declining memory.[ 9 ] It is a

naturally occurring phospholipid that is taken into the body as part of the

normal diet. Phospholipids are a major component of biological membranes.

PS is a minor percentage of the phospholipids that compose biological

membranes, but may be especially important in determining neuronal membrane

surface potential (the electrical potential at the membrane) and local

ionic environment (the mix of electrically charged particles within the

neuron.[ 10 ] Thus, PS is informally characterized as a brain-specific

nutrient because of its possible importance in neuronal functioning. Like

ginkgo, PS can be purchased as an over-the-counter supplement in many

groceries and drugstores. PS has stimulated significant interest in Italy

as a treatment for age-associated and dementia-related memory impairment

and is featured in a tradebook as a memory cure for age-associated memory

impairment.[ 9 ] How might PS promote memory functioning?

 

3.a. Mechanisms and animal studies

PS is thought to be especially vital to the neuron membrane. This membrane

is particularly important for the communication between neurons. Recall

that networks of communicating neurons store memories. Some areas of the

neuron membrane contain receptors responsible for receiving the

neurotransmitter message from other neurons. Other parts of the neuron

membrane allow the neuron to pass the message from one end of the neuron to

the other. This process is a fascinating one in which the cell membrane

essentially transmits an electrical current from one end of itself to the

other.

 

The problem is that as people age, the neuronal membrane changes somewhat

in its composition and starts to lose receptors. Also, the receptors that

are left begin to lose the capacity to receive messages. It is also

possible that the membrane begins to become more “rigid,” so that it cannot

easily transmit the electrical charge along the neuron. It is easy to see

that if these problems become too severe, neurons simply will not pass on

the messages they receive. When communication among neurons is compromised,

the neuron networks that store memories will fail, and memory will decline.

PS seems to help the neuronal membrane resist these age-related changes in

its composition, and possibly even to revitalize itself so that it can

reverse some of them.

 

PS within the neuronal membrane is especially important for the activation

of a particular kinase—protein kinase C (PKC)—that plays a critical role in

learning and memory. As already mentioned, the binding of a

neurotransmitter to certain receptors initiates the production of second

messengers within the neuron. One of these second messengers acts on PKC

within the cytoplasm of the neuron to induce it to move to the cell

membrane, where it becomes activated by binding with calcium and PS. That

is, PS within the membrane is necessary to activate PKC.

 

PKC has many functions within the neuron, including the activation of genes

that are critical in producing the long-term changes involved in memory.

PKC also is involved in regulating the release of neurotransmitters from

neurons, another critical aspect of the neural process that underlies

cognitive function. Neurotransmitter molecules are held in organelles

called synaptic vesicles, with several thousand molecules being in a single

vesicle. These vesicles are loaded into specialized release sites in the

axon terminals called active zones. To release transmitter from the neuron,

the vesicle must move up to and fuse with the neuron´s cell membrane, a

process called exocytosis. This process is quite complex and involves a

large number of proteins. PKC regulates the functioning of a number of

these proteins, and so regulates the release of many different types of

transmitters, one of which is ACh. It is noteworthy that PKC activity

declines with age,[ 11 ] perhaps because of age-related deficits in PS.

 

Research with aging animals has shown that long-term treatment with dietary

PS attenuates and perhaps even eliminates many of the neuronal effects of

aging. For example, we noted earlier that the growth of dendritic spines is

a key substrate of stable long-term memory. There is a loss of dendritic

spines with aging, and this loss is prevented by dietary PS.[ 12 ]

Treatment with PS has also been reported to counteract the reduction in

release of neurotransmitters (e.g., ACh, dopamine, and norepinephrine) that

occurs with aging.[ 13 ]

 

Aging not only reduces the amount of neurotransmitter released by neurons,

but can also lead to reductions in the numbers of receptors that are

present on the membrane surface to receive the neurotransmitter message.

This is likely due to reductions in the expression of the genes that code

for receptors, a reduction that could easily be caused by reductions in

kinase (e.g., PKC) activity. Interestingly, PS has been shown to restore

receptor numbers to normal in aged mice.[ 14 ] Also, PS seems to help the

neuron membrane maintain its charged state[ 10 ] so that it can transmit

its electrical message. Finally, PS may be important for maintaining the

general structure and health of the neuron.[ 10, 15 ] Simply put, PS

supplements might have beneficial effects on memory by allowing neurons in

the neuron networks to keep effectively communicating with one another so

that existing memories can be retained and new memories formed. The theory

is that as people age, they need to supplement the brain with more PS than

they get through their normal diets.

 

Long-term treatment with PS has been reported to restore normal memory in

aged animals on a variety of tasks. Aged animals show declines in learning

and memory on a wide spectrum of tasks, and PS treatment has been broadly

effective. For example, a task called the Morris water maze is used in many

studies of aging. In this task, a rat or a mouse is placed in a circular

tank of water that has been made opaque. A platform is placed in the tank,

but its surface is a few centimeters below the surface of the water so that

it is not visible. Rats and mice do not like being in water, and so the

animal swims about the tank in an effort to find an escape route. It will,

by accident, encounter the platform and climb onto it, thereby escaping the

water. The animal is allowed to stay on the platform for a period of time,

and then placed in the water again. The platform is always in the same

location, and on succeeding trials the rat or mouse is started in different

locations within the tank. The outcome is that the animal learns the

spatial location of the platform by using cues within the room in which the

tank is located, and swims directly to the platform no matter where in the

tank the animal is placed. A large amount of research has shown that the

rat or mouse forms a spatial map of the maze that it uses to guide its

escape, and this map is retained in memory. The animal can be tested days

after training, and it will swim right to the hidden platform. The Morris

water maze is of special interest because it is very sensitive to the

functioning of a particular part of the brain called the hippocampus, a

region that is especially vulnerable to age-related declines. Thus, an

animal with damage to the hippocampus cannot learn and remember this task.

Aging is associated with severe deficits in learning and remembering this

task, and these are reversed by PS treatment.[ 16 ]

 

3.b. Controlled human studies

3.b.i. Effects on patients with moderate cognitive impairments

A handful of double-blind, placebo-controlled, multicenter experiments

examining the effects of PS on memory performance in older humans have been

conducted in Italy.[ 17, 18, 19 ] The subjects in these studies were

older adult patients ranging in age generally from 55 to 80 y and

displaying moderate cognitive decline as assessed by standard screening

tests. Patients with concomitant severe medical conditions, such as

depression, chronic alcoholism, and severe Alzheimer´s disease, were

excluded, as were patients who were taking medications that might mask or

interfere with the possible effects of PS (e.g., other nootropic drugs,

barbiturates, antidepressants, antipsychotics). At each center, patients

were randomly assigned either to treatment with 300 mg of PS per day

(divided into three daily doses of 100 mg each) or to placebo treatment

(e.g., corn oil) for periods ranging from 8 to 24 wk. Sample sizes were

reasonable, ranging from 87 patients[ 18 ] to 388.[ 17 ]

 

Memory tests were administered prior to treatment, at the conclusion of

treatment, and usually at the midpoint of treatment. The various

experiments used similar though not identical tasks measuring immediate and

delayed recall. Short lists of words (5–15) were first auditorily presented

at brisk rates (usually one word every 2 s). Usually the list (or

nonrecalled items of the list) was re-presented to allow multiple recall

trials, and a total recall score, representing combined performance across

all trials, was calculated. Typically the pretreatment recall levels were

used as a covariate, providing a sensitive evaluation of treatment effects.

 

In all these experiments, PS consistently and significantly improved total

recall relative to the placebo treatment for this subject population.

However, the effects were also uniformly modest. More precisely, across the

studies the proportion of words recalled for the placebo groups ranged from

0.36 to 0.60. The PS treatment increased the proportion of recall by just

under 0.03 to just over 0.06 across the studies. This proportion translates

into an increase in total recall of between one and two words. In one case,

this increase was the result of a dynamic whereby the placebo group´s

recall decreased by less than a word from pretreatment to the end of

treatment, and the PS group´s recall increased by less than a word.[ 19 ]

 

Villardita et al.[ 19 ] also reported significant benefits of PS for digit

span (recall of digit lists in either forward or backward order; Palmieri

et al.[ 18 ] did not find significant benefits for digit span) and for

immediate and delayed “cued semantic verbal memory” tests in which

semantically related cues were apparently provided to prompt retrieval of

words. Other memory tests in this study did not uniformly show a

significant advantage of PS. Briefly, the PS and placebo groups showed no

significant difference in immediate and delayed recall of geometric figures

or in delayed recall of a 15-item list.

 

This pattern of no or minimal effects of PS on memory tasks other than

immediate recall of lists of items was echoed in two additional studies

using small numbers of patients. In one study, conducted in the United

States, the patients met criteria for probable Alzheimer´s disease (51

patients),[ 20 ] and in the other study, conducted in Germany, they had a

diagnosis of primary degenerative dementia (33 patients).[ 21 ] The

treatment periods and dosage levels were the same as in the Italian

studies. Unlike the Italian researchers, Engel et al. used a design in

which each participant was tested once after PS treatment and once after

placebo treatment (double crossover design), allowing within-subjects

comparison of PS with placebo treatment. In this study, none of the three

memory tests, including prose and associative-memory tests, showed benefits

of an 8-wk 300-mg/ day PS treatment regimen.

 

Similarly, in the study by Crook et al.,[ 20 ] none of the 10 objective

cognitive and memory tests showed effects of a 12-wk 300-mg/d PS treatment.

Several of the memory items on an interview-based scale (a clinical global

improvement scale) showed a benefit of PS treatment. For a subsample of 33

patients with mildest impairment (scores of 19–23 on the Mini-Mental State

Examination. MMSE; lower scores on this measure indicate more severe

deficits), only a single objective test (one that involved associating

first and last names) showed a significant benefit of PS at the end of the

3-mo treatment period (though again, several memory-related scale items

showed benefits of PS). Clearly, as the authors acknowledged, the

interpretation of this effect is clouded by concerns about the large number

of comparisons conducted. Given that they used a P value of 0.05, rather

than a more stringent value, for establishing significance, the probability

of a type 1 error (concluding that a difference exists when it does not)

was relatively high.

 

In summary, among older adults with cognitive impairment that can be

considered moderate, PS has produced consistently modest increases in

memory performance for a particular recall paradigm (quick presentation of

relatively short lists of items). There is little evidence of positive

memory effects on other memory tests. From all these studies, only one

positive mnemonic effect of PS that could be characterized as sizable

emerged. For the cued semantic verbal memory test, the PS group recalled

about 50% more items than the placebo group after 3 mo of treatment

(proportion of items recalled was 0.64 versus 0.44).[ 19 ]

 

3.b.ii. Effects on normal older adults

In a double-blind, placebo-controlled, multicenter study, Crook et al.[ 22

] investigated the mnemonic effects of PS in a sample of 149 normally aging

adults ranging in age from 50 to 75 y. The participants were considered to

have age-associated memory impairment (i.e., memory decline associated with

normal aging). People with dementia, Alzheimer´s disease, or other

neurological disorders associated with cognitive deterioration were

excluded from the study. Another feature of this study is that memory

testing was conducted 4 wk after the end of the 12-wk treatment, as well as

during the treatment (at 3 wk, 6 wk, 9 wk, and 12 wk). Five memory tests

related to everyday memory use constituted the primary memory evaluation:

learning of name-face associations, delayed recall of the name-face

associations, face recognition, telephone-number recall, and recall of

misplaced objects. The authors designated these tests as primary on the

basis of normative data showing that these tests produce a clear pattern of

age-related decline in performance. Several other memory tests that did not

show such clear age-related decline were used as well and were designated

as secondary (e.g., story recall).

 

Overall, the PS treatment produced modest effects. Acquisition and delayed

recall of name-face associations were significantly improved during the

first 6 weeks of treatment, but these differences did not persist during

the latter half of the 12-wk treatment. Further, these differences were

slight in that they represented about a 1-point improvement over a score of

just over 9 (1 point was given for every name correctly recalled upon being

cued with the face). By the end of the treatment, the PS group

significantly outperformed the placebo group on only one test, the

face-recognition test.

 

More consistent and long-lasting effects of PS were observed in a subgroup

of 57 participants who performed poorly on pretreatment memory tests but

similarly to the other participants on the vocabulary subtest of the

Wechsler Adult Intelligence Scale. For these participants, either

immediately at the conclusion of the treatment or at testing 4 wk after

treatment, there were significant benefits of PS relative to the control

for all the primary memory measures, as well as for story recall. Also,

ratings by a psychologist or nurse showed that this cluster of PS-treated

participants improved more than the placebo group on several items in a

measure of specific cognitive symptoms and overall cognitive status.

 

3.b.iii. Safety

The studies reviewed reported no adverse effects from the PS treatment. In

one study, many of the participants were patients on medication, and PS did

not interact with any of the pharmaceutical drugs that these patients were

taking.[ 17 ] However, patients taking antipsychotics, antidepressants,

barbiturates, methyl-dopa, reserpine, and bromocriptine were excluded from

the study. Thus, there is no evaluation of possible interactions of PS with

all potential pharmaceuticals taken by adults. Crook and Adderly[ 9 ]

recommended against taking PS during pregnancy or lactation and cautioned

that individuals taking anticoagulant medication should be careful with PS.

 

One major safety-related issue concerns the source of the PS. Most studies

used bovine PS, but concerns have since been raised about the possibility

of viral contamination of that source. Accordingly, PS derived from soy

lecithin is now being sold. One possible controversy is whether

plant-derived PS has the same effects as animal-derived PS, although Crook

and Adderly[ 9, 23 ] suggested that soy-based and bovine PS produce

similar mnemonic effects.

 

3.c. Summary

On the basis of the studies just reviewed, clinical studies without

double-blind controls, and clinical observation, some psychologists and

medical professionals advocate the use of PS, sometimes along with other

supplements like ginkgo, for preventing or reversing memory loss associated

with age and age-related dementias.[ 9, 23, 24, 25, 26 ] Some

researchers are quite optimistic about the effects of PS. For example.

Crook and Adderly[ 9 ] concluded that “PS is effective in delaying and

usually reversing age-associated memory impairment” (p. 86). In a review of

nutrients for restoring cognitive function. Kidd[ 23 ] claimed that “PS is

a phospholipid validated through double-blind trials for improving memory,

learning, concentration, word recall, and mood in middle-aged and elderly

subjects with dementia or age-related cognitive decline” (p. 144).

 

In light of the studies just reviewed, we believe that these are overly

generous interpretations of the scientific evidence. PS does produce

effects in the mammalian brain that enhance brain functioning, and it

attenuates age-related deficits in learning and memory in a variety of

animal paradigms. However, the documented mnemonic effects for PS in humans

are limited in a number of critical ways. First, the corpus of studies is

small. Second, within this small set of studies, the effects of PS are not

consistent across different population groups nor across different types of

memory tests. Third, a number of the reported memory increases after PS

treatment, though statistically significant, are modest. We are not

convinced that the modest increases found would necessarily translate into

noticeable differences in memory functioning. Finally, relatively robust

effects of PS, in terms of both the degree and the consistency of the

improvement across a number of memory tests, seem limited to just one small

sample of older adults who had no diagnosed dementias, showed relatively

more age-associated memory decline than their peers, were relatively well

educated, and scored higher than average on subtests of IQ batteries.[ 22 ]

 

These cautionary remarks notwithstanding, in our opinion these preliminary

findings are strong enough to warrant further study and suggest possible

foci for investigation. Older adults with relatively severe age-associated

memory decline might be fruitfully singled out for further study of

possible benefits of PS. More judicious selection of memory tests might be

warranted as well. The list-recall paradigm appears to be consistently

sensitive to PS effects. Reliable replications of these results would

provide a foothold from which to explore and analyze benefits of PS.

Failure to find consistent effects on memory in some studies may be due to

insensitivity in the memory tests used[ 22 ] or to using tests that do not

articulate with the specific memory processes that PS may influence.[ 26 ]

Clearly, most, if not all, of the questions concerning possible memory

benefits of PS remain unanswered. We cannot rule out the possibility that

PS enhances memory for at least some older adults with memory impairment,

but we also cannot confidently conclude that PS has specific positive

effects on memory.