Dementia Dilemma: The Effect of

Anticholinergic Medications on the Aging Brain

Crystal Parry
Independent Research GT
March 8, 2017

Advisor: Chioma Esoga

Dr. Melissa Kiehl
Abstract

A link between anticholinergics and dementia was found recently during a study

conducted on dementia patients. Research indicates that this may be the result of lowered

acetylcholine levels and neuronal damage that happens in the brain after prolonged and frequent

of anticholinergic medications. Acetylcholine supplements have been a suggested solution, but

they lack the potency to make a difference on their own on the cognitive function of dementia

patients. This study will investigate which already existing dementia therapy drugs will be

effective in slowing down dementia symptoms or slowing them down all together in dementia

patients. The results of a meta-analysis on four different studies yielded various results in terms

of which approach to dementia therapy was the best, suggesting that more research is needed in

this area of dementia research in order to reach a conclusion in the overall effectiveness of

acetylcholine supplements.

Introduction

According to the British Museum, the average person will take about 14,000 pills in their

lifetime. This number is expected to rise to 40,000 in the near future. Such habits are concerning

when they have been shown to have a negative impact on the brain. Recent studies have shown

that over the counter medications may cause cognitive decline and diseases like dementia. These

types of medications are called anticholinergics, and work to suppress the nerves in the body.

Researchers believe that using anticholinergics over time can prevent nerves from being able to

function properly. However, acetylcholine supplements are an option for many who want to

prevent themselves from developing dementia in the future. Its ability to reproduce the material

needed to make neurons in the brain make it vital to patients dying of dementia.
 Phosphatidylserine is the best option because of its limited side effects and ability to

reproduce acetylcholine in the brain. This paper will examine the side effects and the ability to

reproduce neurons of four different acetylcholine supplements; phosphatidylserine, Huperzine A,

CDP-Choline, and Bacopa Monnieri. The characteristics of these supplements will be compared

to determine the best supplement that can be paired with existing dementia therapies to reverse

dementia symptoms.

Review of Literature

In todays society there has been a rise in dementia amongst elderly adults, especially in

United States. There is not a definite cause of the start of dementia in the brain, and as a result,

there is ongoing research being conducted to find it. Various studies that claim to have found the

cause of dementia arise everyday, so there is a vast amount of information on this subject.

Recently, there has been research into the effects of anticholinergic medications on the cognitive

abilities of elderly dementia patients. Medical dictionaries define anticholinergics as a

medication that blocks acetylcholine, a neurotransmitter that delivers signals to control bodily

functions (Cafasso, 2016). Acetylcholines special function within the central nervous system in

the brain is threatened by anticholinergics when the nerves in the brain become degenerated.

Damage that occurs specifically in the neocortex of the brain, which is responsible for memory,

eventually leads to dementia (Waymire, J.C., 1997). As a result, researchers believe that by

blocking neurotransmitters, anticholinergics are actually reducing the effects of acetylcholine

within the brain. The potency of an anticholinergic medication is usually rated on a scale of one

to three, with one being the lowest concentration and three being the strongest concentration. If

anticholinergic medications are in fact a cause of dementia, such information will help them,
their families, and physicians make informed decisions about what supplements they can take to

reduce the potential of developing dementia while taking their over-the-counter medications.

Over time, the prolonged use of anticholinergics has been linked to the decline in the

cognitive of older adults. In a study conducted by researchers at the University of Indiana, it was

found that patients who had taken over the counter anticholinergic medications had developed

dementia as a result. One of the lead researchers stated in an interview that patients who had

repeated and frequent use of these medication developed dementia symptoms within a range of

six months to eight years. The researcher also reported that patients had been taking level three

anticholinergics, which are very potent and likely to block neurotransmitters and cause dementia.

(Doheney, K., 2016). Similarly, in the book, Drug-induced Dysfunction in Psychiatry, the author

asserts the notion of the toxicity of anticholinergics due to repeated and highly concentrated

doses. When the level of the drug becomes toxic, the risk of developing dementia

increases(Kennedy J.S., 1992). Another study of a larger magnitude was conducted by

researchers through the Alzheimers Disease Neuroimaging Initiative (ADNI) and the Indiana

Memory and Aging Study (IMAS), in which some of elderly participants, with a mean age of

73.3 years, were given medications with high anticholinergic effects while others were not.

Their brains were later tested for cognitive decline and brain atrophy, symptoms that are

typically seen in dementia patients. Researchers noticed an increase in these symptoms, and

therefore advised patients to discontinue using anticholinergic medications (Risacher et al.,

2016). Not only do these drugs pose a threat to development of dementia in the brain,

anticholinergics have also been linked to the progression of the disease in those who already

have it. At the University of California Medical Center, doctors explain that dementia is
worsened by the severe side effects of anticholinergics, such as hallucinations and drowsiness

(The Regents of the University of California, n.d.).

Alternative antihistamine medications have been prescribed to dementia patients who

need the effects of an anticholinergic without its negative cognitive side effects. Levocetirizine

and Cetirizine are antihistamines that are often suggested to patients to reduce the effects that

anticholinergics would have on the brain. (OmedaRx, 2015). Antihistamines work to prevent the

side effects of colds or allergic reactions, just as antihistamines do, but by preventing the natural

substances created in the body after an allergic reaction from being present in the body. Despite

the reduced impact antihistamines usually have on the cognitive health of an individual, their

side effects can be equally as detrimental to a dementia patient, especially one that is very

elderly. For example, common side effects associated with levocetirizine include drowsiness, dry

mouth, cough, fever, difficulty urinating, and weakness. Cetirizine also has these severe side

effects, and is unable to stop the progression of an allergic reaction like an anticholinergic can.

As a result, many patients who take cetirizine need to have epinephrine (Epipen) on them at all

times. Acetylcholine supplements have also been one of the many proposed solutions to raising

the level of acetylcholine in the brain, and reducing the impact of anticholinergic medications.

Acetylcholine (ACh) found in the brain has a role in creating neurons that are utilized in the

central nervous system of the brain. It works specifically in the neuromuscular junction of the

brain, and is responsible for sending signals to the skeletal muscle and other motor nerves by

distributing itself throughout the nerves, and is therefore responsible for a persons motor skills.

In the cells of the neuromuscular junction is where acetylcholine is synthesized and excreted to

move throughout various pathways in the brain. Degeneration of these pathways is usually the

cause of dementia symptoms, such as lapses in memory, and can be caused by anticholinergic
medications. Damage to the cholinergic receptors become damaged in the neocortex, in the

neuromuscular junction, which is associated with memory loss. As a result, there is a significant

decrease of acetylcholine concentration in the cerebral cortex of the brain when dementia begins

to occur. In fact, there has been a direct link between this event and the development of

Alzheimers disease in the brain (University of Texas Health Center, 1997). Replacing the

acetylcholine that can recreate the neurons and its pathways in the neuromuscular junction has

become a plausible solution to preventing the cognitive problems that are caused by the

degeneration of these pathways. Dr. James Meschino, the Clinical Director at the RenaiSante

Institute of Integrative Medicine also believes that acetylcholine supplements can aid in

improving the cognitive state of a person with dementia, and can even prevent it all together in a

healthy individual. Dr. Meschino proposes four different acetylcholine supplements that can be

possibly prescribed to dementia patients. These supplements are: CDP-choline,

phosphatidylserine, Bacopa Monnieri, and Huperzine A. All of the supplements are naturally

occurring substances, however; CDP-choline and phosphatidylserine are usually found in the cell

membrane of nerves, while Bacopa Monnieri and Huperzine A are plants found in certain

ecosystems in the world. CDP-choline, also called citicoline has been studied in many dementia

patients, and researchers at the Institute for CNS Disorders in Spain analyzed many studies in

which the supplement originated from cell membrane found in the gut wall and liver, and was

administered both orally and intravenously. There appeared to be some benefits, such as the

modulation of neuronal death in the brain. However, researchers found that other studies claimed

citicoline did not always produce the desired effect in the subjects tested. The researchers

concluded that more trials were necessary to determine the effectiveness of citicoline.

Phosphatidylserine, which is also located within cell membrane, is thought to use its fatty acids
to repair the damage caused by dementia. A study conducted on rats at the Yakult Institute

Central Institute of Microbiological Research revealed just how effective phosphatidylserine was

in improving the condition of the senile rats. At first, researchers doubted its ability to restore

cognitive function in the brain, based on previous data they gathered that showed fatty acids in

bovine brain that had been effective in human subjects. However, it was shown that

phosphatidylserine did increase glucose concentrations, which is a critical component in

restoring acetylcholine levels in the brain. Overall, researchers show a potential in

phosphatidylserine reversing the progression of dementia or preventing it from occurring in the

brain altogether. The plant based supplements, Bacopa Monnieri and Huperzine A, had less

success in convincing researchers in their ability to help reproduce acetylcholine. Huperzine A is

a club moss typically found in China, and is used by the elderly who experience memory issues.

The newly licensed drug is extracted from the moss plant and is administered intravenously and

works in the body to inhibit antiacetylcholinerase, an enzyme in the body that prevents

acetylcholine from being created. Huperzine A prevents this enzyme from carrying out its

function in the body so more acetylcholine can be produced. The meta-analysis that authors

conducted shows that Huperzine A also has noncholinergic properties that protect neurons from

oxidation and other injury in the brain (Qian, Z.M. & Ke Y., 2014). Despite these optimistic

results, other studies reveal that Huperzine A may have side effects that could be hard on the

body of an elderly patient. Researchers at the Mayo Clinic of Minnesota claimed that many

participants in studies of Huperzine A suffered negative side effects like vomiting and nausea

(Bauer, B.A., n.d.). The last acetylcholine supplement that was examined is Bacopa Monnieri.

Just like Huperzine A, Bacopa Monnieri is intravenously administered to patients. In a particular

study, a group of rats were administered this acetylcholine supplement for 2 weeks and had to
complete a Morris maze water test, which is often used as a test for memory. The other rats were

given a placebo for the 2 week period and had to complete the same maze. Data from the studied

showed that rats who were given Bacopa Monnieri could complete the Morris maze water test

more quickly than those who had not. However, the results of this study conflicted with the

background research the researchers completed, showing that Bacopa Monnieri doesnt have any

significant positive impact on cognitive development (Uabundit, N., et. al., 2010). In conclusion,

all four acetylcholine supplements displayed somewhat of an ability to effectively reproduce

acetylcholine in the brain. Phosphatidylserine, on the other hand, was the only supplement to

consistently show it was able to reproduce acetylcholine that would be helpful to a brain with

dementia.

The superiority of phosphatidylserine over the other acetylcholine supplements was

established in two different studies conducted on the response of rats to the acetylcholine

supplement. In the first study conducted in 1995 by Italian scientists, rats were first separated by

age; either they were 24 months or 3 months of age. The researchers induced a dementia state in

24-month-old rats by injecting a tris buffer into their brains.Consequently, the acetylcholine

production in their brains were 50% lower than the 3-month-old rats. Then the rats were given

phosphatidylserine over a period over 30 days to repair the damage caused by the tris buffer, but

acetylcholine production was still low. Researchers attribute this to the low doses they gave to

the rats, and concluded that phosphatidylserine must be given in high doses to be effective

(Pedata, et. al., 1985). This was done in another study conducted at the University of Chile.

Researchers published a 40-day study conducted on pregnant female rats, using DHA-

lysophosphatidylserine, a type a phosphatidylserine acetylcholine supplement. The supplement

was administered before and during the rats pregnancy, and when they gave birth, the brains of
their pups were analyzed for 60 days. The amount of acetylcholine produced in the pups

increased in the cerebellum and hippocampus, and they exhibited better memory and learning

skills than the control pups. The results of this study and others on the ability of

phosphatidylserine and its ability to raise acetylcholine levels necessary to combat dementia

supports that it is the best supplement for dementia patients (Valenzuela, A. et. al., 2010).

Phosphatidylserine also lacked serious side effects in the subjects of all the studies that were

analyzed, showing that it has potential for an acetylcholine supplement.

Although phosphatidylserine shows promise for researchers, it still has not been passed

as a dementia therapy drug here in the United States by the FDA. This is due to the lack of a

sufficient amount of trials done on the subject. The director of dietary supplements at the FDA,

Dr. Christine Taylor, addressed researchers who want phosphatidylserine to be approved by

saying that there is not enough scientific evidence to support agreement that phosphatidylserine

may reduce the risk of dementia or cognitive dysfunction in the elderly. She explained that the

science provides very limited and preliminary evidence for qualified health claims about these

relationships. The director also said that this supplement would have to be labeled with this

information so it doesnt mislead consumers. The director also brought up the concern that taking

phosphatidylserine from cows may lead to the spread of viruses (FDA Qualified Health Claim,

2003). This may cause doctors and pharmacists to be wary of prescribing such a medication to

their patients. In an interview conducted with Chioma Esoga, PharmD, a pharmacist at the

University of Maryland Medical Center, this point was also stressed (Appendix A). Ms. Esoga

explained that acetylcholine supplements such as phosphatidylserine are only about 20%

effective in reproducing neurons in the brain. Acetylcholinerase, an enzyme in the brain, is

present to break down acetylcholine, so even though excessive amounts of acetylcholine may be
present in the brain, most of it will be broken down before it can create neurons (Esoga, C.

personal communication, January 9,2017). So, this doubt surrounding phosphatidylserine would

need to be alleviated for patients to take it. One way this may happen is that if phosphatidylserine

is administered along with other dementia therapy drugs that are already administered to patients.

In such a situation, phosphatidylserine may enhance the amount of overall acetylcholine that is

produced in the brain.

Acetylcholine supplements like phosphatidylserine can be a breakthrough for those

struggling with dementia and its effects. However, when paired with another medication, its

potential to increase acetylcholine in the brain can be maximized so it can work to reverse the

symptoms felt by all dementia patients. The use of these supplements can therefore save the

millions who are diagnosed with dementia every year, and should be seriously considered as an

option for treatment.

Research Methods and Data Collection

To determine the effectiveness of phosphatidylserine and its pairing with other current

dementia therapy drugs, meta-analysis was used while analyzing 4 different studies conducted by

researchers on the topic. The studies were found using internet searches on medical journal

databases. Then, the studies were annotated and compared to one another using a graphic that

compared its ability to answer key research questions, as well as how well the results show the

effectiveness of phosphatidylserine on dementia symptoms (Appendix B). The studies were all

conducted on elderly individuals who had dementia or experienced dementia like symptoms.

Results and Data Analysis

Throughout the data analysis process, data sources were evaluated on how well they

answered these research questions: How effective was the treatment in alleviating dementia
symptoms experienced by subjects? What effect did side effects have on the patients cognitive

response to the treatment? The original hypothesis was that treatments that incorporated

phosphatidylserine and dementia therapy drugs that have already been successfully used on

patients would work the best in reducing the cognitive symptoms that dementia patients

experience. In Source #1, researchers combined a total of 23 studies to evaluate the

phosphatidylserine treatment. The studies only had low to moderate evidence suggesting the

effectiveness of the phosphatidylserine on Alzheimers disease and dementia was not significant.

There was virtually no improvement to the patients capacity for activities of daily living.

Cognitively, patients did not improve significantly, in behavior, or verbal memory scores,

suggesting that phosphatidylserine was not able to make a significant impact on the cognitive

health of the participants. Researchers conducted a 95 % confidence interval that showed that

there was little to no evidence that the cognitive function of the patients had improved.

Therefore, a correlation between the two variables could not be determined. Additionally, side

effect and their impact on patients were also not reported, making the results of the study

questionable. Source #2 was a similar study, which was a review of studies published on

citicoline, a precursor to phosphatidylserine, which works in conjunction with the acetylcholine

supplement to increase the levels of acetylcholine in the brain. Most of the studies showed a

positive impact of the use of phosphatidylserine on patients, especially with prolonged use and

high dosages. Researchers showed that the increase in phosphatidylserine caused an increase in

the acetylcholine levels in the brain, resulting in reduced neuronal death and more enhanced

neuroprotection in the brain. Learning, memory, and motor skills all improved in patients as a

result. On the other hand, this source did not address the possible side effects that dementia

patients may have endured while using this treatment, which makes the source less credible.
Source #3 was a clinical review of studies similar to that of source #2, and still evaluated the

effectiveness of citicoline and phosphatidylserine being used in conjunction. The studies

revealed that citicoline was rapidly absorbed and used by the brain to create new neurons in the

cortex of the brain. The amount of acetylcholine overall also increased in the hippocampus of the

brain. Cognitive and motor recovery was also reported to have occurred within 6 months in the

subjects of the studies. In terms of the side effects, researchers reported that there was no change

in the blood chemistry, organ histology, or urinary parameters of the patient. So, these clinical

trials were better than the studies conducted in the first two sources, since the side effects on

patients were reported and appeared to not have any negative impact on the patients. Source #4,

the last source that was analyzed, was a study conducted on 174 outpatients of a dementia

therapy program, who were 65 years or older, and had been diagnosed with mild dementia or

Alzheimers disease. Researchers hypothesized that a combination of the commonly used

dementia therapy drug, Rivastigmine, and citicoline would be the most effective in raising

acetylcholine levels in the brain, which was based on other studies they had read on the topic. No

significant differences were made in the cognitive function of the patients, however; an increase

in organic chemicals such as noradrenaline and dopamine, helped to improve the moods of

patients. Researchers did not observe any side effects in the patients of this study since

Rivastigmine and citicoline were administered in such low doses.

Discussion and Conclusion

The rise of dementia and other cognitive related health issues being reported amongst the

elderly population has become a health crisis in the world, especially here in the United States.

The projected impact of the number of people with dementia could be more than we even realize,

which is why research that attempts to determine the cause of dementia and how it can be solved
will be beneficial to pharmaceutical researchers of dementia therapy drugs and the doctors that

prescribe them to their patients. The research questions that were answered by the meta-analysis

show that there are varying results in terms of the effectiveness of acetylcholine supplements and

their ability to raise acetylcholine levels in the brain needed to restore cognitive function in

elderly dementia patients, while doing so in a way that will not have such negative side effects

that would weaken patients. Meta-analysis also limited the types of sources that were available

for research, as well as the quality of the source being used. As time goes on, more quality

research will be needed to truly explore the way dementia therapy drugs and supplements like

phosphatidylserine can be used to alleviate the cognitive problems faced by many senior citizens

in this country and around the world today.

 References

Bauer, B. A. (Ed.). (n.d.). Can huperzine A prevent memory loss and improve cognitive

function in people with alzheimer's disease? Retrieved January 3, 2016, from

http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/expert-

answers/huperzine-a/faq-20058259

Cafasso, J. (2016, October 10). All about anticholinergics. In G. Krucik (Ed.), Heathline.

Retrieved October 12, 2016, from

http://www.heathline.com/health/anticholinergics

Common meds and dementia: How strong is the link? (Interview by K. Doheney)

[Transcript]. (2016, May 9). Retrieved October 12, 2016, from WebMD website:

http://www.webmd.com/allergies/news/20160509/anticholinergic-drugs-

dementia-link?page=3

Dublin, S., & Larson, E. B. (2015, June 30). What if youre taking an anticholinergic

Medication [Blog post]. Retrieved from Healthy Findings Blog:

http://tinyurl.com/gp2jzvc

FDA. (2003, May 13). Qualified health claim: Final decision letter - phosphatidylserine

and cognitive dysfunction and dementia. Retrieved December 21, 2016, from U.S.

Food & Drug Administration

website:http://www.fda.gov/ForConsumers/ByAudience/ForWomen/FreePublicati

ons/ucm072999.htm

Garca-Cobos, R., Frank-Garca, A., Gutirrez-Fernndez, M., & Dez-Tejedor, E. (n.d.).

 Citicoline, use in cognitive decline: Vascular and degenerative. Journal of the

Neurological Sciences. http://dx.doi.org/10.1016/j.jns.2010.08.027

Marcus, M. B. (2016, April 21). Popular drugs for colds, allergies, sleep linked to

dementia [Newsgroup post]. Retrieved from http://www.cbsnews.com/news/

Masashi, S., Hideyuki, Y., & Satoshi, K. (2009, April). Pharmalogeffects of

phosphatidylserine enzymatically synthesized from soybean lecithin on brain

function in rodents. Retrieved from Journal of Nutritional Science and

Vitaminology database. (Accession No. http://doi.org/10.3177/jnsv.42.47)

OmedaRx. (2015, March). Safer alternatives to potentially high risk medications in the

elderly [Table]. Retrieved from

https://www.asuris.com/documents/10192/286192/

Pedata, F., Giovannelli, L., Spignoli, G., Giovannini, M.G., & Pepeu, G. (1985).

Phosphatidylserine increases acetylcholine release from cortical slices in aged

rats. Retrieved from Neurobiology of Aging database. (Accession No.

http://dx.doi.org/10.1016/0197-4580(85)90013-2)

Qian, Z. M., & Ke, Y. (2014, August). Huperzine A: Is it an effective disease-modifying

drug for alzheimer's disease? Retrieved from U.S. National Library of Medicine

database. (Accession No. 10.3389/fnagi.2014.00216)

Risacher, S. L., McDonald, B. C., Tallman, E. F., West, J. D., Farlow, M. R., Unverzagt,
 F. W., . .. Saykin, A. J. (2016). Association between anticholinergic medication

use and cognition, brain metabolism, and brain atrophy in cognitively normal

older adults [Abstract]. JAMA Neurology, 73(6).

http://dx.doi.org/10.1001/jamaneurol.2016.0580

The Regents of the University of California. (n.d.). Anticholinergic medications:

Frontotemporal dementia. In Frontotemporal dementia. Retrieved October 5,

2016, from http://memory.ucsf.edu/ftd/medical/treatment/avoid/multiple

Uabundit, N., Wattanathorn, J., Mucimapura, S., & Ingkaninan, K. (2010, January).

Cognitive enhancement and neuroprotective effects of bacopa monnieri in

alzheimer's disease model. Retrieved from Science Direct database. (Accession

No. http://dx.doi.org/10.1016/j.jep.2009.09.056)

University of Texas Health Center at Houston. (1997). Acetylcholine neurotransmisson.

In J. C.Waymire (Author), Neuroscience online: An electronic textbook for the

neurosciences. Retrieved November 14, 2016, from

http://neuroscience.uth.tmc.edu/s1/chapter11.html

Valenzuela, A., Nieto, S., Sanhueza, J., Morgado, N., Rojas, I., & Zanartu, P. (2010,

March). Supplementing female rats with DHA-lysophosphatidylcholine increases

docosahexaenoic acid and acetylcholine contents in the brain and improves the

memory and learning capabilities of the pups. Retrieved from Academic

Repository of the University of Chile database. (Accession No.

10.3989/gya.053709)
 Appendix

Appendix A

Interview on 1/9/17 with Chioma Esoga, PharmD

Crystal: Okay, so I just wanted to ask you a few questions about acetylcholine supplements since

I am doing a research project on how they can reverse dementia symptoms.

Chioma Esoga: Okay.

Crystal: So, I was wondering; how effective they are in terms of reproducing neurons in the

brain?

Chioma Esoga:Wellyou know it can help, but if Im looking at it percentage wise, maybe only

about 20%.

Crystal: Oh really?

Dr.Esoga: Yes. You cannot trust the supplements to do the work, you know what Im saying?

And you also have herbal supplements which have not really gone through FDA, so as a

pharmacist, and youre giving supplements, like the herbal supplements, to patients like

citicoline and Bacopa Monnieri and phosphatidylserine-all those things I see, well they have

some use, but they are not what we would say that its one hundred percent supposed to do the

work. Because the brain is a very diverse area, and acetylcholine is a neurotransmitter that does a

lot of work, that works on a lot of receptors like the muscle receptors that are responsible for a

lot of muscle movement, memory, learning-a very large spread. So yes, if the problem is, since

there are different causes of dementia, if the main problem is that there is not enough

acetylcholine in the system, there arent enough neurotransmitters or maybe the primary receptor

thats supposed to help this thing [dementia], is not functioning well, it doesnt matter how much
acetylcholine you keep pouring into the system, theres always going to be that rate limitance in

the brain thats going to affect it adversely. So, for instance, there is an enzyme called that breaks

down the acetylcholine--

Crystal: Yes Ive heard of it, acetylcholinesterase, right?

Chioma Esoga: Yes, so if this enzyme is suddenly multiplied exponentially in the brain, and you

want to help with dementia, if the patient is not taking a medication that will stop this enzyme

from multiplying as it is, it doesnt matter how many supplements or acetylcholine youre

pouring into the system because those enzymes are always there to break down, which is what it

has to do. So in instances of that, you would need a medication that will inhibit this enzyme; that

will stop this enzyme from manufacturing exponentially in a way that its not supposed to. Do

you get what Im saying?

Crystal Parry: Yes, okay.

Chioma Esoga: Then once you do that, then you can add all these acetylcholine supplements to

kind of help provide acetylcholine, you know? But its not just one thing [supplements] you

know? So its now two drugs working together. So what Im trying to say is, its not the end all be

all to treat dementia. So thats they have other drugs that go through FDA like Namenda,

Donepezil, Galantaminethere are all these medications that does different work. The thing

about how the body works, when there is a problem, its best to identify where the problem is.

The minute you can figure out what is the cause, and you can address that cause, then the

addition of supplements can come into play, just to serve as extra [treatment]. So, I mean in the

hospital where I practice, we allow patients to take these herbal supplements, but when they are

admitted we dont because we are trying to eliminate things that can bring on issues. Because,

you know, whatever you take, it can cause some kind of issue. Although its providing something,
too much of that thing can lead to something bad. So its always good to identify where the cause

is, and when it comes to dementia, it can be a lot of things. It could be that theres too many

enzymes, theres some kind of mutation in the cells, it could be that the receptors are not

responding as much as they should, you know? It could be different stuff. Its always good to

identify what those particular things are, and prescribe certain medication, and then just add

supplements as extra.

Crystal Parry: So even with some of them like phosphatidylserine inhibitor, it wont do much to

reproduce neurons those neurons in the brain?

Choima Esoga: Well, you know that there are a million neurons in the brain, right? And it might

help, but its just not automatically going to reverse or help with total reproduction. Because in

the phosphatidylserine will just help in one aspect of cell building. It only makes like one block

of the cell. So there are other things that are needed to help. Im not saying that its not going to

help. It will help. It has its place in therapy.

Crystal Parry: Alright.

Chioma Esoga: But not like 100%, not like 50%-- I would say maybe 35%. Its providing the

building blocks that the cell needs, but after you build that block there is a lot more that needs to

happen. Because even if you build the block and cells are fine, the neurons are fine, the enzyme

is still there. So, its always going to be there, it doesnt matter how much you build up the

neurons, the enzyme is always going to be there to destroy them. So, thats why you need other

medications or other drugs in place to help this thing [supplements]. The reason why some

people who have high blood pressure are on multiple medications because each medication

targets something different, which helps to manage the blood pressure. The same analogy applies

for brain functiondementia is a vast, complex disease in the brain, so that supplements alone
are not enough to address the whole problem. So, you need something else to play a role and

compensate for the supplements as well.

Crystal Parry: So what else can be done to improve the performance of acetylcholine

supplements in the brain?

Choima Esoga: Well, there are many therapies that can be added to what the supplements do in

the brain just as it is done with dementia patients in hospitals. I would suggest exploring some of

those mechanisms to have a better understanding of how they can work together in improving

the state of dementia patients. You could also look at how therapies such as these can improve

the role of supplements in improving dementia.

Crystal Parry: That sounds interestingI will definitely look into that. And thank you for your

help.

Chioma Esoga; anytime! You can also email me with any more questions if more issues come up.

Crystal Parry: Okay, thanks! Bye!

Chioma Esoga: Goodbye.

Appendix B
Source Source #1 Source #2 Source #3 Source #4

Methods A combination of a A review of A review of A study

total of 23 studies published studies clinical trials in performed on
on elderly patients on the impact of the cognitive decline 174
with early stage use of citicoline, a on the impact of outpatients
Alzheimers precursor to citicoline on the who were 65
disease and phosphatidylserine, cognitive function years or
vascular dementia on cognitive of elderly older, and
function in elderly dementia patients were
patients diagnosed
with
Alzheimers
disease or
mild
dementia

Results Studies only had Most of the studies Studies revealed Although that
low to moderate showed a positive that citicoline was other studies
evidence impact of the use of rapidly absorbed led
suggesting the phosphatidylserine and used by the researchers to
effectiveness of the on patients, brain to create new hypothesize
phosphatidylserine especially with neurons in the that a
on Alzheimers prolonged use and cortex of the brain. combination
disease and high dosages. Amount of of dementia
dementia was not Increase in acetylcholine also therapy drugs
significant. phosphatidylserine increased in the and citicoline,
Researchers caused an increase hippocampus of would be the
conducted a 95 % in the acetylcholine the brain. most
confidence interval levels in the brain, Cognitive and effective in
that showed that resulting in reduced motor recovery raising
there was little to neuronal death and was also reported acetylcholine
no evidence that more enhanced to have occurred levels in the
the cognitive neuroprotection in within 6 months. brain, their
function of the the brain. Learning, research
patients had memory, and motor proved
improved. A skills all improved otherwise.
correlation in patients.
between the two
variables could not
be determined.
 Effectiveness of There was Citicoline, by The magnitude of No
Treatment virtually no creating improvement was significant
improvement to phosphatidylserine, greater in differences
the patients was able to raise Alzheimers were made in
capacity for levels of disease patients the cognitive
activities of daily acetylcholine in the was statistically function of
living. Cognitively, brain of patients, significant, the patients,
patients did not but did more so in according to however an
improve younger patients researchers, increase in
significantly, in since acetylcholine showing that organic
behavior, or verbal synthesis is slower treatments may chemicals
memory scores, in younger brains. have actually had a such as
suggesting that Patients also positive impact on noradrenaline
phosphatidylserine experienced better the cognitive and
was not able to moods since health of patients. dopamine,
make a significant organic chemicals Memory and helped to
impact on the responsible for attention increased improve the
cognitive health of regulating emotions in the treatment moods of
the participants. had increased. groups of all the patients.
studies compared
to the groups given
a placebo.

Reported side effects Side effects to the Side effects were Researchers Rivastigmine
patients were not not mentioned for reported that there and citicoline
mentioned in the experimental was no change in were
study, making the groups, making the blood administered
results results of the study chemistry, organ in forms that
questionable as to questionable. histology, or lowered its
its effects on the urinary parameters toxicity, so
patient. of the patient. very few side
effects were
observed in
the patients.
Conclusions/Limitations The study had little The study The study showed The study had
convincing emphasized that that the use of a small
evidence to show citicoline and citicoline raised sample size in
that phospholipids like the phospholipid comparison
phosphatidylserine phosphatidylserine concentrations to others,
was effective in work best when necessary to create which could
restoring cognitive used in older the affect the
function in the individuals when phosphatidylserine outcome of
brain on its own. used by patients. used to make the results of
Therefore, it may acetylcholine. P- the study. It
not be useful for values were also did nothing
preventing within the to improve
dementia and other significance level, the cognitive
cognitive diseases. showing that the health for
There was also studies used were patients other
some discrepancies reliable. than to
in the effectiveness improve
of citicoline, which mood,
had differing showing that
results in two of the it is not
studies. effective in
raising
acetylcholine
levels.

Source #1:
The Cochrane Collaboration. (2013). Cognitive training and cognitive rehabilitation for mild to

moderate Alzheimer's disease and vascular dementia (Review). US National Library of

Medicine. doi: 10.1186/alzrt189

Source #2:

Conant, R., & Schauss, A. G. (March 2004). Therapeutic applications of citicoline for stroke

and cognitive dysfunction in the elderly: A review of the literature. BioMedSearch.

Source #3:

Garcia-Cobos, R., Frank-Garcia, A., Gutierrez-Fernandez, M., Diez-Tejedor, E. (August 2010).

Citicoline, use in cognitive decline: Vascular and Degenerative. Journal of the

Neurological Sciences. doi: 10.1016/j.jns.2010.08.027

Source #4:

Castagna, A., Cotroneo, A. M., Ruotolo, G., Gareri, P. (September 2016). The CITRIVAD study;

Citicoline plus rivastigmine in elderly patients affected with dementia study. CrossMark.

doi: 10.1007/s40261-016-0454-3