CMT and AD: A Jumble of Letters Bound for

Change
By Sosie Yorki
 Yorki 2

Sosie Yorki

Greene

Capstone

16 January 2017

CMT and AD: A Jumble of Letters Bound for Change

I. Introduction

While attending the Summer Research Apprenticeship Program in the University of

Wyoming last summer, I conducted research with a neuroscience professor about Huntingtons

disease. I became fascinated with the human brain and its network of neurons, so I wanted to

center my capstone project on neurological diseases. I didnt pinpoint the diseases to focus on

until I found my mentor, Krista Qualmann, who is a genetic counselor at Memorial Hermann.

She introduced me to the disease she specializes in, Charcot-Marie-Tooth (CMT), which

degrades patients hands, feet, and leg muscles. I decided to make it a topic for my capstone

project because although 2.8 million people worldwide are diagnosed with CMT, its still widely

unknown.1 When patients receive their diagnosis, they are lost and confused. In addition, the

disease doesnt receive enough funding for research and as a result, there still isnt a drug or cure

for CMT. Because CMT mainly affects nerves in the lower body, making CMT my only topic

would make me miss out on the research I originally wanted to do about neuroscience.

Therefore, I also chose to look at Alzheimers disease (AD), which affects the mental health of

5.4 million senior citizens in America alone.2 Its prevalent, debilitating to patients, and

mysterious in the way it works. Research on AD gives me further insight on how the human
 Yorki 3

brain and nerves interact with one another, and research on CMT teaches me how the nervous

system and muscles interact.

The frequency, and thus the burden, of AD and CMT disease will increase as the worlds

population does. The burden of these diseases does not only rest on the patient, but individuals

close to the patient and a nation as a whole. On an individual level, Alzheimers and CMT

obstruct a patient from performing daily tasks, which in turn puts stress on the loved ones taking

care of him, who are informal caregivers. This stress can lead to depression and deterioration of

health for the informal caregivers as they worry about the patient.3 On a national level, federal

healthcare programs spend enormous amounts of money assisting those who cant help

themselves. For example, in 2011, Medicare spent $11 billion on helping those with Alzheimers

pay for their medical expenses.4 While there is not as much research about CMT spending, its

known that a notable amount of social security disability benefits goes towards CMT patients.5

Without a cure for these diseases, patients have no other option than to find a way to afford

costly treatment options and thus put a drain on federal assistance programs. But the amount of

money spent on victims of CMT and AD through Medicare and social security benefits does not

reflect the total amount of economic loss by these diseases. Patients usually end up losing their

jobs and informal caretakers could work less hours, work less productively, take unpaid leaves of

absence, or retire early.6 These possible contributors to the economy cannot work to their full

potential and end up making less money for themselves and putting less money in the nations

circulation.

The burden of CMT and AD arent only present in America, but in other less developed

countries (LDCs) as well. The rate of AD is increasing the fastest in LDCs, but with lower

quality of doctor training, little to no equal access to medical care, and a focus on communicable
 Yorki 4

and neonatal diseases, AD patients do not receive enough care to improve or maintain their

condition.7 In developed countries, doctors are better aware of AD, diagnose it earlier, and are

more likely to meet with their patients regularly. 7 This same pattern can be assumed with CMT,

where patients have better access to treatment in more developed countries than LDCs. Patients,

regardless of income, deserve to have quality treatment to make their AD or CMT more

tolerable. Donations to international research organizations, such as the CMTA (CMT

Association) and Alzheimers Association, would help equalize access to a better life for CMT

and AD patients across the globe.

We, as global citizens, must accept and support the research community by donating to

Alzheimers and CMT organizations that fund their research. We must not be afraid of scientific

advancements and instead open our minds to new possible cures, no matter how seemingly

controversial. It is our responsibility to support new findings for these neurodegenerative

diseases, or diseases that break down neurons, and to pressure the scientific community into

action by increasing awareness.

II. Neurons and Neurodegenerative Diseases

To perform tasks such as walking, blinking, and lifting, our brain communicates with our

muscles via messenger carriers called nerve cells, or neurons. When we decide we want to do

something, our brain sends out a message in the form of electrical bursts or molecules called

neurotransmitters. Nerve cells receive the message and send out their own (called a nerve

impulse) to the muscles involved in the action we want to perform. For example, if one wants to

walk across a room, his brain will send a message, which can be neurotransmitters or bursts of
 Yorki 5

electricity, out to the nearest neuron. That neuron will pass the message along to other neurons in

a chain until the message reaches ones leg muscles.

Neurons are all connected to one another in long chains from the brain to every muscle.

Each neuron has long, fingerlike extensions called axons that reach out to the neighboring

neuron, and there are tiny spaces called synapses between the axon and neighbor. It looks like a

line of people standing side to side with their arms out. Each person is almost holding hands with

the person next to him, but there is space between adjacent peoples fingers. This space is where

neurons release and receive neurotransmitters. Synapses are necessary for neurons to function

properly, because if a neuron cant release neurotransmitters, it cant perform its function.

Neurons also need their outer covering, called the myelin sheath, to protect the cell.

The spontaneous and damaging breakdown of neurons seen in CMT and AD is called

neurodegeneration. Neurodegenerative diseases can affect nerves in the brain, causing decreased

mental capacity, or throughout muscles in the body, causing loss of function. CMT and AD are

caused by neurodegeneration, but how neurodegeneration occurs in each disease causes the

different symptoms.

III. Neurodegeneration in Alzheimers and CMT

Alzheimers

Neurodegeneration in AD happens exclusively in certain regions of the brain.

Alzheimers is caused by a deformation in a protein called tau and blockages called amyloid

plaques. To understand how tau works, we must discuss neurofibrils. Neurofibrils are small

fibers that act like the skeleton of the neuron. They are train tracks for nerve impulses, or

electrical messages, to travel on. The tau protein makes sure that the neurofibrils lie in parallel,
 Yorki 6

orderly rows so it can function properly. In Alzheimers, the tau protein is deformed and forms

tangles with the neurofibrils. Amyloid plaques, or clusters of a protein called amyloid, are

another cause of Alzheimers.8 These plaques exist in synapses and block the space neurons need

to send messages to one another, so the affected neurons stop working.

CMT

Neurodegeneration in CMT happens in neurons that cause movement in the hands, feet,

and legs. There are plenty of conditions that induce neurodegeneration, but one that is of special

interest to scientists is mitochondrial dysfunction. Mitochondria are organelles within neurons

that undergo chemical processes to provide neurons with the energy needed to function. CMT

patients contain a genetic mutation in a gene called Mfn2 that makes mitochondria smaller than

normal and forces the organelle to produce less energy. Without enough energy to keep itself

alive, the neuron will break down.8 Neurons in CMT and AD break down in, and thus affect,

different parts of the body.

IV. Symptoms of Alzheimers and CMT

Alzheimers

Alzheimers patients can experience both physical and mental changes. Mental symptoms

include delusions, hallucinations, agitation, anxiety, and memory loss, because the neurons in the

frontal cortical brain lobe and anterior cingulate cortex that support emotional capability

degenerate as the disease progresses.9 In addition, an AD patient may exhibit an odd

phenomenon called mental age regression, which means that the patient ages backwards

mentally.10 For example, if one day an 80 year old patient no longer recognizes the 40 year old

daughter who has been taking care of him, its because he thinks he is at an age where his
 Yorki 7

daughter was younger than 40. The patient may think he is 50 years old, which is when his

daughter was only 10. The patient wont recognize the daughter at the present time, but if one

shows him pictures of his daughter when she was 10, he will remember her and may wonder

where she is.

Physical symptoms of Alzheimers include difficulty in talking, abnormal posture and

gait, and muscle rigidity.11 Although the exact brain region where these functions are controlled

and how they are affected by AD is unknown, physical symptoms, or motor signs, predict how

severe ones AD will be. Patients with motor signs are more likely to be institutionalized and

require pricier treatments, but little correlation has been seen between motor signs and cognitive

and functional decline.12

CMT

Symptoms of CMT include muscle weakness and numbness. A group of scientists at

Oxford University found that patients with the most common subtype of CMT, CMT1A,

experience muscle weakness almost exclusively in muscles near the feet and that the weakness

progresses from muscles that straighten limbs to muscles that bend at the joints. This data

suggests that CMT1A degenerates in a length-dependent pattern where only long neurons present

in the feet and legs are affected.13 The same group also claims that loss of sensitivity could be

explained by the degeneration of sensory axons, or the extensions of neurons that make

organisms feel pain.13 Patients of CMT tend to experience sleep apnea, a condition where ones

breathing is interrupted while asleep, and depression, but scientists still dont know why.14 These

two side effects could result from the drastic change in lifestyle one experiences when he

develops CMT or from neurological impairment, but less data supports the latter.14
 Yorki 8

V. Risk Factors and Diagnosis

Symptoms of CMT and AD can worsen if the patient has risk factors, which are the

conditions that increase ones risk of contracting a disease. Right now, doctors just use risk

factors to determine if someone will get a disease, but this knowledge about risk factors can be

expanded to improving the current inefficient diagnosis system for CMT and Alzheimers.

Alzheimers

Risk factors for Alzheimers include heart and brain conditions that are common among

middle-aged adults. Hypertension is a risk factor because it impairs blood flow and directly

induces neurodegeneration decades before symptoms of AD will show. 15 Depression, traumatic

brain injury, alcoholism, and smoking also increase ones risk of developing AD because these

conditions decrease mental and brain health. 16 On the surface, risk factors may seem like they

dont play a huge role in disease onset, but its projected that if there was 10%-25% less people

who had one of the seven risk factors for AD common in middle-aged adults (diabetes,

hypertension, obesity, smoking, depression, low educational attainment, and physical

inactivity), there would be 17.2 million less cases in the world.17 ADs risk factors explain why

the disease is so prominent in America since there are high rates of depression, hypertension,

alcoholism, and smoking in adults.

Senior citizens with Alzheimers usually are not diagnosed in time for treatment to improve

their quality of life. Since the symptoms of AD are similar to those of Parkinsons,

frontotemporal dementia, Huntingtons, and other forms of dementias, the only real defining

characteristic of the disease is the presence of malfunctioning tau proteins and amyloid plaques

in the brain.18 Therefore, doctors either rely on brain imaging and neurological, cognitive, and
 Yorki 9

neuropsychological tests (which is only around 85% accurate), or wait until the patient reaches a

somewhat defining characteristic of the disease, dementia, to diagnose it. 19,20,21 At this point,

treatment is useless since patients have already faced severe memory loss and are dependent on a

caretaker. Doctors should be able to accurately diagnose AD once earlier symptoms, such as a

decline in memory and psychosis, arise, but currently cant because early symptoms can be

confused with other diseases. ADs early symptoms can be recognized by requiring 50 year-old

patients with two or more risk factors (as determined by ones doctor) to take tests that measure

attention, memory, and language skills once every six months until decreased ability starts to

show.

CMT

CMTs risk factors come from defects in the peripheral nervous system, or the network of

nerves throughout the body, excluding those in the brain. Certain vitamin deficiencies can

damage nerves and prevent muscles from functioning properly. For example, lack of vitamin

B12, which is a building block for the myelin sheath, can degrade the outer layer of neurons.22

Vitamin B6 and E deficiency can cause the symptoms of CMT seen in the feet, such as

numbness, high arches, and burning pain.22 People who stray from a recommended, healthy diet

are at risk for vitamin deficiency. Supplements are affordable and easily accessible in drug

stores, so doctors should suggest for patients with CMT in their family history to take them.

Vitamin deficiency alone is not an indicator of CMT, but it can still be considered by doctors

and should be tested before diagnosing patients. The symptoms of CMT are similar to those of

multiple muscular disorders, so doctors can use inexpensive urine tests to see if patients have

both the vitamin deficiencies and the symptoms before narrowing the diagnosis down to CMT. If

patients show symptoms of a muscular disorder without vitamin E, B12, or B6 deficiencies, then
 Yorki 10

doctors can assume they dont have CMT. This method is cheaper and faster than the current

method of diagnosis. Urine test results come back to the patient in three days maximum, but

genetic tests and nerve biopsies (the extraction a nerve for analysis to see if it shows a pattern of

degradation specific to CMT),23 which are the current tests doctors order for possible CMT

patients, take about a month for the results and data analysis to be processed. Urine tests are also

cheaper as they can be bought in drug stores, while nerve biopsies and genetic testing can cost

over hundreds of dollars in out-of-pocket expenses.

VI. Current Treatments

Not only is the method for diagnosis of CMT and AD being improving, but the treatments

are as well. To develop a new drug or treatment, scientists synthesize it in their lab, test it on

animals numerous times, and finally test it on humans to prove it is safe. This extensive process

prevents many drugs from reaching pharmacies, and even when a new drug is approved, it could

still be proven ineffective years later. CMT and AD currently have approved treatments but not

cures.

Alzheimers

There are two classes of drugs that are currently on the market to treat Alzheimers:

memantine and cholinesterase inhibitors. Memantine blocks neurons receptors and prevents

them from receiving glutamate, a neurotransmitter that, when overproduced, can overexcite

neurons, waste their energy, and cause them to degenerate. Memantine has proven to slow

dementia and, when combined with other drugs such as donepezil, maintain cognition. In
 Yorki 11

addition, AD patients find memantine tolerable and its side effects (which are headaches,

constipation, and dizziness) mild.24

Cholinesterase inhibitors (ChE-Is) can come in the form of a pill, syrup, or patch. They work

by preventing the breakdown of acetylcholinesterase, a neurotransmitter that is vital for memory

and is mistakenly degraded in Alzheimers. ChE-Is improve cognitive ability in patients;

however, the improvement doesnt last for long. As AD progresses, neurons produce less of

acetylcholinesterase, so ChE-Is have less of the neurotransmitter to maintain. The disease

progresses to a point where the amount of acetylcholinesterase produced is not enough to keep

the patients cognition at a healthy level. 25 Patients find the side effects of ChE-Is, which include

nausea, diarrhea, vomiting, and anorexia, less tolerable than those of memantine. 26 Memnatine is

currently the preferred AD medicine among patients.

Outside of drugs, caregiving can be considered a form of treatment because caregivers soothe

patients and make their AD more tolerable. The U.S currently employs a nursing home system

for AD patients, but residents of the home lack one-on-one care, and nursing homes are costly.

Therefore, some people have turned to seeking care in other countries such as Thailand, where

professional caregiving is cheaper and culture mandates that nursing homes use one-on-one

methods to help the patient.27 Buddhism, which is prominent in Thailand, emphasizes the

importance of karma, which implies that if ones elder falls ill, its because he and his elders

deeds in their past lives have caused the elder to fall ill and him to become his caregiver.26

Because of these Buddhist beliefs, Thai caregivers could take their job more seriously as it is

seen as a spiritual obligation instead of a way to make a living. Caregiving needs to be reformed

in the U.S because it is something that will always be needed, even if better treatments are found.

The U.S should try to improve their nursing home system by employing more nurses and giving
 Yorki 12

incentives for companies to pay them more in order to give the ultimate care to AD patients and

reassurance to informal caregivers that their loved one will get quality care.

CMT

Treatments for CMT include rehabilitation, corrective surgery, orthopedic braces, exercise,

and pain and fatigue management, which treat symptoms and are not perfect remedies. In

rehabilitation, physical therapy has high risks for patient injury and could worsen muscle

weakness if the patient is overworked.28 Corrective surgery normalizes high-arched feet, hand

deformities, and scoliosis,28 but surgery could go wrong and does not work for all patients. When

I conducted field work with a genetic counselor, I was able to consult with patients and meet one

whose surgical procedure went wrong. Her surgery was supposed to lower the arch in her foot,

but her arch ended up heightening and she began experiencing more pain than before. Patients

that do not want to undergo surgery turn to ankle-foot orthoses, which help patients control their

foot better and normalize their gait, and crutches, which prevent them from falling. If the patient

is experiencing weakness in their arms or hands, they may do exercises that involve stretching

rubber bands and stretching putty to strengthen their forearm and fingers. For any patient

experiencing pain and fatigue, doctors prescribe drugs specialized for neuropathy-related

symptoms.29

An interesting, natural form of treatment for CMT, called Ayurvedic treatment, can be found

in India. In a phone call interview with Krista Qualmann, M.S. (January 2017), I learned that this

treatment involves taking various herbs, such as Ashwagandha (which stimulates nerve activity)

and Boswellia (which can decrease inflammation in the feet), in a pill form. Although these

treatments are not popular in the American market, they can viewed as examples by the scientific
 Yorki 13

community for possible drugs that can be developed to treat CMT. Future treatments are looking

to minimize side effects in CMT and the chance of failure in AD.

VII. Future Treatments

Alzheimers

Scientists are looking into microtubule (MT) stabilizing agents as a cure for Alzheimers. In

AD, deformities in the tau protein tangle up microtubules, which are the train tracks for

neurotransmitters. They are alongside neurofibrils and a part of the neurons skeleton. MT-

stabilizing agents promote order in microtubules by removing tau from or changing the structure

of MTs. Since MT-stabilizing agents come from natural sources such as tree sap and bacteria,

they are not likely to cause harsh side effects and could prevent or cure AD.29 Scientists struggle

when trying to make MT-stabilizing agents into drugs because they must ensure the treatment

only targets front lobe neurons. In addition, scientists have to experiment with what stage of AD

is most effective to start prescribing MT-stabilizing drugs. After MT-stabilizing agents are tested

on humans and proven safe, it will still face issues with getting approval from the general public

and the FDA.

Genetic modification is another type of possible controversial treatment being looked at for

Alzheimers. By changing the mutations in our genetic code that cause us to develop AD,

scientists can essentially eliminate AD for all those who can afford it. In Europe, genetic

modification is undergoing intense research, and three years ago, 11 new locations in our DNA

where mutations determine Alzheimers disease have been found. 30 This approach towards

changing our genes can be seen in CMT research as well.

 Yorki 14

CMT

A future cure for CMT could be gene therapy, which is the removal or suppression of the

problematic mutation that causes the disease. This possible treatment is being heavily researched

in the U.S., Italy, and Japan, where they have the money for such costly experiments.28,31 It

sounds foolproof, since CMT is caused by mutations, but getting the foreign genes past the

bodys immune system and the chance of adversely inducing other genetic diseases are obstacles

to the development of gene therapy. 28 Current advancements in technology today allow for gene

therapy to become a reality, but the modification of DNA raises questions about ethics.

Therefore, this new therapy receives little support from the public and the Food and Drug

Administration (FDA), which approves medications before they can be prescribed.

Although gene therapy is of huge controversy, drugs are not. Pharnex, a pharmacy company

in France, is testing a combination of three drugs (baclofen, naltrexone, and sorbitol) that has

shown to increase myelination, or the process of building the outer protective layer of neurons

that degenerate in CMT1A. The combination of the drugs, called PXT-3003, does this by

suppressing the pmp-22 gene, which contains the mutation that onsets demyelination. PXT-3003

could be the future of possible cures for CMT as it showed no side effects in lab mice and has

proven to be the most promising potential treatment. 32 For now, the future for PXT-3003 will be

uncertain until further testing is done on humans.

VIII. Conclusion

Even though the U.S is at the global forefront of research, there is still a great need for

collaboration among research institutions around the world. Due to cultural differences and
 Yorki 15

access to different resources, scientists of every country approach treatments and research

differently. Although a country may not be as advanced in medical treatment as the U.S. and

other wealthy countries, it still has a valuable perspective to offer towards advancing research.

As stated by Alzheimers Disease International, A sustained global effort is thus required to

promote action on dementia [, or Alzheimers, and CMT] and address the challenges posed by

[these diseases] and [their] impacts. No single country, sector or organization can tackle this

alone.7 By using other countries as inspiration or employing the perspective of different

cultures, the U.S can advance CMT and AD research even further and come up with a cure

within the next few decades. But before the U.S. collaborates with other countries, we must gain

domestic approval from the public.

With basic knowledge of science, some of the general public sees scientific research as

playing God and are fearful towards it. With support for new scientific breakthroughs, the

people will show desire for change and can influence the FDA to approve new treatments and

cures. Although the future of treatments for CMT and Alzheimers, such as gene therapy, may

seem scary, change must be welcomed in order to advance society. People must vocalize their

support, spread it to others, and show that that they arent afraid.

Support for the scientific community begins with awareness and can be continued with

constant donations. With increased awareness, more patients will be concerned about CMT, and

doctors will be coerced to learn about and specialize in the disease. More pressure will be placed

on scientists to find a cure and donations to charities such as the CMT Association and

Alzheimers Association will help properly fund scientific research.

 Yorki 16

References
1. What is CMT? Charcot-Marie-Tooth Association Web site.

http://www.cmtausa.org/understanding-cmt/what-is-cmt/. Published June 6, 2016.

Accessed January 6, 2017.

2. 2016 Alzheimers Disease Facts and Figures. Alzheimers Association Web site.

http://www.alz.org/facts/. Published 2016. Accessed January 6, 2016.

3. Clyburn LD, Stones MJ, Hadjistavropoulos T, Tuokko H. Predicting Caregiver

Burden and Depression in Alzheimers Disease. Journal of Gerrontology: Social

Sciences. 2000; 55(1): S2-S13.

http://psychsocgerontology.oxfordjournals.org/content/55/1/S2.full.pdf.

4. Hurd MD, Martorell P, Delavande A, Mullen KJ, Langa KM. Monetary Costs of

Dementia in the United States. The New England Journal of Medicine. 2013; 368:

1326-1334. doi: 10.1056/NEJMsa1204629.

5. Carter GT, Han JJ, Abresch RT, Jensen MP. The Importance of Assessing Quality of

Life in Patients with Neuromuscular Disorders. American Journal of Hospice and

Palliative Medicine. 2007; 23: 493-497. doi: 10.1177/1049909106295278.

6. Neal MB, Wagner DL. Working Caregivers: Issues, Challenges, and Opportunities

For the Aging Network. NFCSP Issue Brief. 2002; 1: 1-12.

http://archives.pdx.edu/ds/psu/15447.

7. Alzheimers Disease International. World Alzheimer Report 2015: The Global Impact

of Dementia. http://www.worldalzreport2015.org/downloads/world-alzheimer-report-

2015.pdf. Published August, 2015. Accessed January 9, 2017.

 Yorki 17

8. Itoh K, Nakamura K, Iijima M, Sesaki H. Mitochondrial Dynamics in

Neurodegeneration. Trends in Cell Biology. 2013; 23(2): 64-71. doi:

10.1016/j.tcb.2012.10.006.

9. Mega M, Lee L, Dinov I, Mishkin F, Toga A, Cummings J. Cerebral Correlates of

Psychotic Symptoms in Alzheimers Disease. Journal of Neurology, Neurosurgery &

Psychiatry. 2000; 69(2): 167-171. doi: 10.1136/jnnp.69.2.167.

10. Lokko HM, Stern TA. Regression: Diagnosis, Evaluation, and Management. The

Primary Care Companion for CNS Disorders. 2015; 17(3). doi:

10.4088/PCC.14f01761.

11. Tsolaki M, Kokarida K, Iakovidou V, Stilopoulos E, Meimaris J, Kazis A.

Extrapyramidal Signs and Symptoms in Alzheimers Disease: Prevalence and

Correlation with The First Symptom. American Journal of Alzheimers Disease and

Other Dementias. 2001; 16(5): 268-278. doi: 10.1177/153331750101600512.

12. Scarmeas N, Albert M, Brandt J, et al. Motor signs predict poor outcomes in

Alzheimers disease. Neurology. 2005; 64(10): 1696-1703. doi:

10.1212/01.WNL.0000162054.15428.E9.

13. Krajewski, KM, Lewis, RA, Fuerst, Dr, et al. Neurological Dysfunction and Axonal

Degeneration in CharcotMarieTooth Disease Type 1A. Brain. 2000; 123 (7): 1516-

1527. doi: http://dx.doi.org/10.1093/brain/123.7.1516

14. Cordeiro J, Marques W, Hallack JEC, Osrio FL. Charcot-Marie-Tooth Disease,

Psychiatric Indicators and Quality of Life: A Systematic Review. ASN Neuro. 2014;

6(3): e00145. doi: 10.1042/AN20130048.

 Yorki 18

15. Kivipelto M, Helkala EL, Laakso MP, et al. Midlife Vascular Risk Factors and

Alzheimers Disease in Later Life: Longitudinal, Population Based Study. British

Medical Journal. 2001; 322: 1447-14451.

doi: http://dx.doi.org/10.1136/bmj.322.7300.1447.

16. Solomon A, Mangialasche F, Richard E, et al. Advances in the Prevention of

Alzheimers Disease and Dementia. Journal of Internal Medicine. 2014; 275(3): 229-

250. doi: 10.1111/joim.12178.

17. Barnes DE, Yaffe K. The Projected Impact of Risk Factor Reduction on Alzheimers

Disease Prevalence. The Lancelet: Neurology. 2011; 10(9): 819-828. doi:

10.1016/S1474-4422(11)70072-2.

18. Dementia and Related Disorders. Alzheimers Community Care Web site.

http://www.alzcare.org/dementia. Accessed January 9, 2017.

19. Albert MS, DeKosky ST, Dickson D, et al. The Diagnosis of Mild Cognitive

Impairment due to Alzheimers Disease: Recommendations from the National

Institute on Aging- Alzheimers Association Workgroups On Diagnostic Guidelines

for Alzheimers Disease. Alzheimers & Dementia. 2011; 7(3): 270-279. doi:

10.1016/j.jalz.2011.03.008.

20. Georgeanopoulou DG, Chang L, Nam JW, et al. Nanoparticle-based detection in

cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimers disease.

Proceedings of the National Academy of Sciences of the United States of America.

2004; 102(7): 2273-2276. doi: 10.1073/pnas.0409336102.

 Yorki 19

21. Perret-Liaudet A, Pelpel M, Tholance Y. Risk of Alzheimers Disease Biological

Misdiagnosis Linked to Cerebrospinal Collection Tubes. Journal of Alzheimers

Disease. 2012; 31(1): 13-20. doi: 10.3233/JAD-2012-120361.

22. Hammond N, Wang Y, Dimachkie M, Barohn R. Nutritional Neuropathies.

Neurology Clinics. 2013; 31(2): 477-489. doi : 10.1016/j.ncl.2013.02.002.

23. Li X, Zi X, Li L, et al. Rapid Genetic Screening of Charcot-Marie-Tooth Disease

Type 1A and Hereditary Neuropathy with Liability to Pressure Palsies Patients.

Neural Regeneration Research. 2012; 7(32): 2522-2527. doi: 10.3969/j.issn.1673-

5374.2012.32.006.

24. Bajic V, Milovanovic ES, Spremo-Potparevic B, et al. Treatments of Alzheimers

disease: Classical Therapeutic Approach. Current Pharmaceutical Analysis. 2016;

12(2): 82-90. doi: 10.2174/1573412911666150611184740.

25. Cummings JL. Cholinesterase Inhibitors: A New Class of Psychotropic Compounds.

American Journal of Psychiatry. 2000; 157: 4-15. doi:

http://dx.doi.org/10.1176/ajp.157.1.4.

26. Cummings JL. Use of Cholinesterase Inhibitors in Clinical Practice: Evidence-Based

Recommendations. American Journal of Geriatric Psychiatry. 2003; 11(2): 131-145.

doi: http://dx.doi.org/10.1097/00019442-200303000-00004.

27. Schenone A, Nobbio L, Bragadin MM, Ursino G, Grandis M. Inherited Neuropathies.

Current Treatment Options in Neurology. 2011; 13: 160-179. doi: 10.1007/s11940-

011-0115-z.

28. Ballatore C, Brunden K, Huryn DM, Trojanowski JQ, Lee V, Smith AB. Microtubule

Stabilizing Agents as Potential Treatment for Alzheimers Disease and Related

 Yorki 20

Neurodegenerative Tauopathies. Journal of Medical Chemistry. 2012; 55(21): 8979-

8996. doi: 10.1021/jm301079z.

29. Subgranon R, Lund DA. Maintaining Caregiving at Home: A Culturally Sensitive

Grounded Theory of Providing Care in Thailand. Journal of Transcultural Nursing.

2000; 11(3): 166-173.

http://journals.sagepub.com/doi/pdf/10.1177/104365960001100302.

30. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74,046

individuals identifies 11 new susceptibility loci for Alzheimers disease. Nature

Genetics. 2013; 45(12): 1452-1458. doi: 10.1038/ng.2802.

31. Maeda MH, Mitsui J, Soong BW, et al. Increased gene dosage of myelin protein zero

causes Charcot-Marie-Tooth disease. Annals of Neurology. 2012; 71(1): 84-92. doi:

10.1002/ana.22658.

32. Ekins S, Litterman NK, Arnold RJG, et al. A brief review of Charcot-Marie-Tooth

research and priorities. F1000 Research. 2015; 4: 53. doi:

10.12688/f1000research.6160.1