Category Archives: Treatment

The Yack on NAC (N-Acetyl-Cysteine) and Parkinson’s

“Once you choose hope, anything’s possible.” Christopher Reeve

“Hope is like a road in the country; there was never a road, but when many people walk on it, the road comes into existence.” Lin Yutang

Introduction: N-Acetyl-Cysteine (or N-acetylcysteine, usually abbreviated NAC and frequently pronounced like the word ‘knack’) is an altered (modified by an N-acetyl-group) form of the sulfur-containing amino acid cysteine (Cys).  NAC is one of the building blocks for the all important antioxidant substance glutathione (GSH).   GSH is a powerful reagent that helps cells fight oxidative stress.  One of the putative causes of Parkinson’s is oxidative stress on dopamine-producing neurons (see figure below). This post summarizes some of the biochemistry of NAC and GSH.  Furthermore, NAC may provide some neuroprotective benefit as a complementary and alternative medicine (CAM) approach to treating Parkinson’s.

“Losing the possibility of something is the exact same thing as losing hope and without hope nothing can survive.” Mark Z. Danielewski

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 Glutathione (GSH):  GSH is a 3-amino acid substance (tripeptide) composed of Cys linked to glutamate (Glu) and followed by glycine (Gly). NAC would need to be de-acetylated to provide Cys and that would feed in to the reaction synthesis. Importantly, Cys is the rate limiting reactant, which means without adequate amounts of Cys you do not make GSH.   The schematic below gives the orientation and order of addition of the three amino acid components to give you GSH.

NACtoGSH

There are two advantages of NAC over Cys for making GSH: (i) the sulfhydryl group of NAC remains reduced (that is as an SH group) more so than the SH group of Cys; and (ii) the NAC molecule appears to transport itself through cell membranes much more easily than Cys.  The reduced (i.e.,  free SH group) form of GSH, once synthesized within the cell, has several key functions that range from antioxidant protection to protein thiolation to drug detoxification in many different tissues.   The key function of GSH is to provide what is known as “reducing equivalents” to the cell, which implies an overall key antioxidant effect.

The schematic below shows NAC transport from extracellular to intracellular (inside the cell), and the primary reactions for detoxification and thiolation from GSH. Implied by this figure below is that GSH is not easily transported into the cell. Furthermore, in a more toxic/hostile environment outside of the cell, you can easily oxidize 2 GSH molecules to become GSSG (the reduced SH group gets oxidized to form an S-S disulfide bond) and GSSG does not have the antioxidant effect of GSH.   However, inside the cell, GSH is a very potent antioxidant/detoxifying substance. And the beauty of being inside the cell, there is an enzyme called GSH-reductase that regenerates GSH from GSSG.

Rushworth-NAC.review-4.2

To recap and attempt to simplify what I just said, NAC gets delivered into a cell, which then allows the cell to generate intracellular GSH.  The presence of intracellular GSH gives a cell an enormous advantage to resist potentially toxic oxidative agents. By contrast, extracellular GSH has a difficult path into the cell; and is likely to be oxidized to GSSG and rendered useless to help the cell.

“Just remember, you can do anything you set your mind to, but it takes action, perseverance, and facing your fears.”  Gillian Anderson

One of many biological functions of NAC:   Perhaps the most important medical use of NAC is to help save lives in people with acetaminophen toxicity, in which the liver is failing.  How does NAC do this?  Acetaminophen is sold as Tylenol.  It is also added to compounds that are very important for pain management ()analgesics), including Vicodin and Percocet. Acetaminophen overdose is the leading cause of acute liver failure in the USA.   This excess of acetaminophen rapidly consumes the GSH in the liver, which then promotes liver death.  NAC quickly restores protective levels of GSH  to the liver, which hopefully reverses catastrophic liver failure to prevent death.

Systemically, when taken either orally or by IV injection, NAC would have 2 functions.  First, NAC replenishes levels of Cys to generate the intracellular antioxidant GSH (see schemes above).  Second, NAC has been shown to regulate gene expression of several pathways that link oxidative stress to inflammation.  Since the primary goal of this post relates to NAC as a CAM in Parkinson’s, I will not expand further on the many uses of NAC in other disease processes.  However, listed at the end are several review articles detailing the numerous medicinal roles of NAC.

“Love, we say, is life; but love without hope and faith is agonizing death.” Elbert Hubbard

Use of NAC as a CAM in Parkinson’s:   This is what we know about oxidative stress in Parkinson’s and the potential reasons why NAC could be used as a CAM in this disorder, it goes as follows  (it’s also conveniently shown in the figure at the bottom):

1. Substantia nigra dopamine-producing neurons die from oxidative stress, which can lead to Parkinson’s.

2.What is oxidative stress? Oxidative stress happens when your cells in your body do not make/have enough antioxidants to reduce pro-oxidants like free radicals. Free radicals cause cell damage/death when they attack proteins/cell membranes.

3.We speak of oxidative stress in terms of redox imbalance (which means the balance between increased amounts of oxidants or  decreased amounts of antioxidants).

4.Glutathione (GSH) is a key substance used by cells to repair/resist oxidatively damaged cells/proteins.

5.”Forces of evil” in the brain that make it difficult to resist oxidative stress:  decreased levels of GSH,  increased levels of iron and  increased polyunsaturated fatty acids.

6.Extracellar GSH cannot be transported easily into neurons, although there is evidence GSH gets past the blood brain barrier;

7.N-acetyl Cysteine (NAC), is an anti-oxidant and a precursor to GSH.  NAC gets through the blood brain barrier and can also be transported into neurons.

8.Cysteine is the rate-limiting step for GSH synthesis (NAC would provide the cysteine and favor synthesis of GSH).

9.Animal model studies have shown NAC to be neuroprotective.

10. Recent studies have shown NAC crosses the human blood brain barrier and may be a useful PD-modifying therapy.

 

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“You cannot tailor-make the situations in life but you can tailor-make the attitudes to fit those situations.”  Zig Ziglar

Scientific and clinical support for NAC in treating Parkinson’s: Content presented here is meant for informational purposes only and not as medical advice.  Please remember that I am a basic scientist, not a neurologist, and any use of these compounds should be thoroughly discussed with your own personal physician. This is not meant to be an endorsement  because it would be more valuable and important for your neurologist to be in agreement with the interpretation of these papers.

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To evaluate the use of NAC in Parkinson’s, Katz et al. treated 12 patients with Parkinson’s with oral doses of NAC twice a day for two days.   They studied three different doses of 7, 35, and 70 mg per kilogram. For example, in a person weighing 170 pounds, from a Weight Based Divided Dose Calculator (click here), this would be 540, 2700, and 5400 mg/day of NAC for 7, 35, and 70 mg/kg, respectively. Using cerebral spinal fluid (CSF), they measured levels of  NAC, Cys, and GSH at baseline and 90 minutes after the last dose. Their results showed that there was a dose-dependent range of NAC as detected by CSF. And they concluded that oral administration of NAC produce biologically relevant CSF levels of NAC at the three doses examined; the doses of oral NAC were also well-tolerated.  Furthermore, the patients treated with NAC had no change in either motor or cognitive function. Their conclusions support the feasibility of using oral NAC as a CAM therapy for treatment of Parkinson’s.

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In a separate study, Monti at al  presented some preliminary evidence for the use of NAC in Parkinson’s. The first part of their study consisted of a neuronal cell system that was pre-treated with NAC in the presence of the pesticide rotenone as a model of Parkinson’s.   These results showed that with NAC there was more neuronal cell survival after exposure to rotenone compared to the rotenone-treated cells without NAC. The second part of the study was a small scale clinical evaluation using NAC in Parkinson’s. These patients were randomized and given either NAC or nothing and continued to use their traditional medical care. The patients were evaluated at the start and after three months of receiving NAC; they measured dopamine transporter binding and  performed the unified Parkinson’s disease rating scale  (UPDRS) to measure clinical symptoms. The clinical study revealed an increase in dopamine transporter binding in the NAC treatment group and no measurable changes in the control group. Furthermore UPDRS scores were significantly improved in the NAC treatment group compared to the control patient group.   An interesting feature of this study was the use of pharmaceutical NAC, which is an intravenous (IV) medication and they also used 600 mg NAC tablets. The dose used was 50 mg per kg mixed into sterile buffer and infused over one hour one time per week. In the days they were not getting the IV NAC treatment, subjects took 600 mg NAC tablets twice per day.

 Okay, what did I just say? I will try to summarize both of these studies in a more straightforward manner.   The results above suggest that NAC crosses the blood brain barrier and does offer some anti-oxidative protection. In one study, this was shown by increased levels of both GSH and Cys dependent on the NAC dose. In another study, they directly measured dopamine transporter binding, which was increased in the presence of NAC. In the second study using a three month treatment strategy with NAC, there was a measurable positive effect on disease progression as measured by UPDRS scores.  

“Our greatest weakness lies in giving up. The most certain way to succeed is always to try just one more time.” Thomas A. Edison

Potential for NAC in treating Parkinson’s: Overall, both studies described above suggest the possibility that NAC may be useful in treating Parkinson’s. However, in both cases these were preliminary studies that would require much larger randomized double-blind placebo-controlled trials to definitively show a benefit for using NAC in treating Parkinson’s. On a personal note, I have been taking 600 mg capsules of NAC three times a day for the past year with the hope that it is performing the task as outlined in this post. Using information from the first study that would be a NAC dose of 24 mg per kilogram body weight. In conclusion, the information described above suggests that NAC may be useful in regulating oxidative stress, one of the putative causes of Parkinson’s. As with all studies, time will tell if ultimately there is a benefit for using NAC in Parkinson’s.

“I am not an optimist, because I am not sure that everything ends well. Nor am I a pessimist, because I am not sure that everything ends badly. I just carry hope in my heart. Hope is the feeling that life and work have a meaning. You either have it or you don’t, regardless of the state of the world that surrounds you. Life without hope is an empty, boring, and useless life. I cannot imagine that I could strive for something if I did not carry hope in me. I am thankful to God for this gift. It is as big as life itself.” Vaclav Havel

References Used:
Katz M, Won SJ, Park Y, Orr A, Jones DP, Swanson RA, Glass GA. Cerebrospinal fluid concentrations of N-acetylcysteine after oral administration in Parkinson’s disease. Parkinsonism Relat Disord. 2015;21(5):500-3. doi: 10.1016/j.parkreldis.2015.02.020. PubMed PMID: 25765302.

Martinez-Banaclocha MA. N-acetyl-cysteine in the treatment of Parkinson’s disease. What are we waiting for? Med Hypotheses. 2012;79(1):8-12. doi: 10.1016/j.mehy.2012.03.021. PubMed PMID: 22546753.

Monti DA, Zabrecky G, Kremens D, Liang TW, Wintering NA, Cai J, Wei X, Bazzan AJ, Zhong L, Bowen B, Intenzo CM, Iacovitti L, Newberg AB. N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson’s Disease: Preliminary Clinical and Cell Line Data. PLoS One. 2016;11(6):e0157602. doi: 10.1371/journal.pone.0157602. PubMed PMID: 27309537; PMCID: PMC4911055.

Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K, Laurie C, Gendelman HE. Neuroinflammation, Oxidative Stress and the Pathogenesis of Parkinson’s Disease. Clin Neurosci Res. 2006;6(5):261-81. doi: 10.1016/j.cnr.2006.09.006. PubMed PMID: 18060039; PMCID: PMC1831679.

Nolan YM, Sullivan AM, Toulouse A. Parkinson’s disease in the nuclear age of neuroinflammation. Trends Mol Med. 2013;19(3):187-96. doi: 10.1016/j.molmed.2012.12.003. PubMed PMID: 23318001.

Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014;141(2):150-9. doi: 10.1016/j.pharmthera.2013.09.006. PubMed PMID: 24080471.

Taylor JM, Main BS, Crack PJ. Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem Int. 2013;62(5):803-19. doi: 10.1016/j.neuint.2012.12.016. PubMed PMID: 23291248.

Cover photo credit: https://s-media-cache-ak0.pinimg.com/originals/e8/33/ae/e833aeb408a432d419628c803bf14498.jpg

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9 Things to Know About Exercise-induced Neuroplasticity in Human Parkinson’s

“A willing mind makes a hard journey easy.” Philip Massinger

“Lack of activity destroys the good condition of every human being.” Plato

Introduction: Much of my life has been spent exercising. Most of this exercise has been done with sheer delight.  Since receiving my Parkinson’s diagnosis, my opinion of exercise has changed.  With Parkinson’s, I’m now exercising as if my life depends on it.  Why?  Animal models (mouse and rat) of Parkinson’s have convincing shown the effect of exercise-induced neuroplasticity.  These animal studies demonstrated neuroprotection and even neurorestoration of Parkinson’s.  But we’re neither mice/rats nor are we an animal model of Parkinson’s disease; thus, this post is an update on exercise-induced neuroplasticity in human Parkinson’s.

“If you don’t do what’s best for your body, you’re the one who comes up on the short end.” Julius Erving

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9 Things to Know About Exercise-induced Neuroplasticity in Human Parkinson’s: Neuroplasticity,  neuroprotection and neurorestoration are catchy words that populate a lot of publications, blogs from many of us with Parkinson’s and from professionals who study/work in the field of Parkinson’s.  It is important for you to develop your own opinion about exercise-induced neuroplasticity. My goal in this post is to provide the basic elements, concepts and key reference material to help you with this opinion. Here is a 1-page summary of “9 Things to Know About Exercise-induced Neuroplasticity in Human Parkinson’s” (click here to download page).

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(1) Parkinson’s Disease (PD): Parkinson’s is a neurodegenerative disorder. Parkinson’s usually presents as a movement disorder, which is a slow progressive loss of motor coordination, gait disturbance, slowness of movement, rigidity, and tremor.  Parkinson’s can also include cognitive/psychological impairments. ~170 people/day are diagnosed with Parkinson’s in the USA; the average age of onset is ~60 years-old.

(2) Safety First: The benefit of an exercise routine/program will only work if you have (i) talked about it with your Neurologist and have his/her consent; (ii) you have received advice from a physical therapist/certified personal trainer about which exercises are ‘best’ for you; and (iii) you recognize that PD usually comes with gait and balance issues, and you are ready to begin. Safety first, always stay safe!

(3) Exercise: Exercise is activity requiring physical effort, carried out especially to sustain or improve health and fitness. Exercise is viewed by movement disorders clinicians, physical therapists, and certified personal trainers as a key medicinal ingredient in both treating and enabling patients at all stages of Parkinson’s.

(4) Brain Health: With or without Parkinson’s disease, taking care of your brain is all-important to your overall well-being, life-attitude, and health. For a balanced-healthy brain, strive for: proper nutrition and be cognitively fit; exercise; reduce stress; work and be mentally alert; practice mindfulness/meditation; sleep; and stay positive.

(5) Neuroplasticity: Neuroplasticity describes how neurons in the brain compensate for injury/disease and adjust their actions in response to environmental changes. “Forced-use exercise” of the more affected limb/side can be effective in driving neural network adaptation.  Ultimately, this can lead to improved function of the limb/side.

(6) Synapses are junctions between two nerve cells whereby neurotransmitters diffuse across small gaps to transmit and receive signals.

(7) Circuitry: A key result of neuroplasticity is the re-routing of neuronal pathways of the brain along which electrical and chemical signals travel in the central nervous system (CNS).

(8) Parkinson’s-specific Exercise Programs:
PWR!Moves (click here to learn more)
Rock Steady Boxing (click here to learn more)
LSVT BIG (click here to learn more)
Dance for PD (click here to learn more)
LIM Yoga (click here to learn more)
Tai Chi for PD (click here to learn more)

What types of exercise are best for people with Parkinson’s disease? Here is a nice overview of the benefits of exercise for those of us with Parkinson’s  (click here). Regarding the PD-specific exercise programs,  I am most familiar with PWR!Moves, Rock Steady Boxing and LSVT BIG (I’m certified to teach PWR!Moves, I’m a graduate of LSVT BIG, and I’ve participated in Rock Steady Boxing). A goal for you is to re-read ‘Safety First’ above and begin to decide which type of exercise you’d benefit from and would enjoy the most.

(9) Brain/Behavior Changes: The collective results found increase in corticomotor excitability, increase in brain grey matter volume, increase in serum BDNF levels, and decrease in serum tumor necrosis factor-alpha (TNFα) levels. These results imply that neuroplasticity from exercise may potentially either slow or halt progression of Parkinson’s.

What the terms mean: Corticomotor describes motor functions controlled by the cerebral cortex (people with Parkinson’s show reduced corticomotor excitability). Brain grey matter is a major component of the central nervous system consisting of neuronal cells, myelinated and unmyelinated axons, microglial cells, synapses, and capillaries. BDNF is brain-derived neurotrophic factor, which is a protein involved in brain plasticity and it is important for survival of dopaminergic neurons. Tumor necrosis factor-alpha (TNFα) is an inflammatory cytokine (protein) that is involved in systemic inflammation.  Some studies of exercise-induced neuroplasticity in human Parkinson’s found the above-mentioned changes, which would imply a positive impact of exercise to promote neuroplastic changes.

What can you do with all of the cited articles listed at the end? Compiled below are some comprehensive and outstanding reviews about exercise-induced neuroplasticity in Parkinson’s.  Looking through these papers, you’ll see years of work, but this work has all of the details to everything I’ve described.

“All life is an experiment. The more experiments you make the better.” Ralph Waldo Emerson

What I believe about neuroplasticity and exercise in Parkinson’s: [Please remember I am not a physician; definitely talk with your neurologist before beginning any exercise program.]  I think about exercising each day; I try to do it on a daily basis.  As a scientist, I’m impressed by the rodent Parkinson’s data and how exercise promotes neuroplasticity. The human studies are also believable; sustained aerobic exercise induces neuroplasticity to improve overall brain health. “Forced-use exercise” is an important concept; I try to work my right-side (arm and leg), which are slightly weaker and stiffer from Parkinson’s. Initially, I used my left arm more, now I ‘force’ myself on both sides with the hope my neural network is stabilized or even improving. If you enjoy exercising as I do, I view it as both an event and a reward; ultimately, I believe it can work and improve my response to Parkinson’s. If you don’t enjoy exercising, this may be more of a task and duty; however, the benefits over time can be better health. Exercise is good for you (heart and brain).  Begin slow, make progress, and see if you are living better with your disorder.  Remain hopeful and be both persistent and positive; try to enjoy your exercise.

“I am not afraid of storms for I am learning how to sail my ship.” Louisa May Alcott

Past blog posts: Both exercise itself and the benefit of exercise-induced neuroplasticity have been common themes for this blog, including (click on title to view blog posting):
Believe in Life in the Presence of Parkinson’s;
Déjà Vu and Neuroplasticity in Parkinson’s;
Golf And Parkinson’s: A Game For Life;
The Evolving Portrait of Parkinson’s;
Believe In Big Movements Of LSVT BIG Physical Therapy For Parkinson’s;
Meditation, Yoga, and Exercise in Parkinson’s;
Exercise and Parkinson’s.

“Do not let what you cannot do interfere with what you can do.” John Wooden

References on neuroplasticity and exercise in Parkinson’s:
Farley, B. G. and G. F. Koshland (2005). “Training BIG to move faster: the application of the speed-amplitude relation as a rehabilitation strategy for people with Parkinson’s disease.” Exp Brain Res 167(3): 462-467 (click here to view paper).

Fisher, B. E., et al. (2008). “The effect of exercise training in improving motor performance and corticomotor excitability in people with early Parkinson’s disease.” Arch Phys Med Rehabil 89(7): 1221-1229 (click here to view paper).

Hirsch, M. A. and B. G. Farley (2009). “Exercise and neuroplasticity in persons living with Parkinson’s disease.” Eur J Phys Rehabil Med 45(2): 215-229 (click here to view paper).

Petzinger, G. M., et al. (2010). “Enhancing neuroplasticity in the basal ganglia: the role of exercise in Parkinson’s disease.” Mov Disord 25 Suppl 1: S141-145 (click here to view paper).

Bassuk, S. S., et al. (2013). “Why Exercise Works Magic.” Scientific American 309(2): 74-79.

Lima, L. O., et al. (2013). “Progressive resistance exercise improves strength and physical performance in people with mild to moderate Parkinson’s disease: a systematic review.” Journal of Physiotherapy 59(1): 7-13 (click here to view paper).

Petzinger, G. M., et al. (2013). “Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease.” Lancet Neurol 12(7): 716-726 (click here to view paper)..

Ebersbach, G., et al. (2015). “Amplitude-oriented exercise in Parkinson’s disease: a randomized study comparing LSVT-BIG and a short training protocol.” J Neural Transm (Vienna) 122(2): 253-256 (click here to view paper).

Petzinger, G. M., et al. (2015). “The Effects of Exercise on Dopamine Neurotransmission in Parkinson’s Disease: Targeting Neuroplasticity to Modulate Basal Ganglia Circuitry.” Brain Plast 1(1): 29-39 (click here to view paper).

Abbruzzese, G., et al. (2016). “Rehabilitation for Parkinson’s disease: Current outlook and future challenges.” Parkinsonism Relat Disord 22 Suppl 1: S60-64 (click here to view paper).

Hirsch, M. A., et al. (2016). “Exercise-induced neuroplasticity in human Parkinson’s disease: What is the evidence telling us?” Parkinsonism & Related Disorders 22, Supplement 1: S78-S81 (click here to view paper)

Tessitore, A., et al. (2016). “Structural connectivity in Parkinson’s disease.” Parkinsonism Relat Disord 22 Suppl 1: S56-59 (click here to view paper).

“If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health.” Hippocrates

“Life is complex. Each one of us must make his own path through life. There are no self-help manuals, no formulas, no easy answers. The right road for one is the wrong road for another…The journey of life is not paved in blacktop; it is not brightly lit, and it has no road signs. It is a rocky path through the wilderness.” M. Scott Peck

Cover photo credit: http://paper4pc.com/free-seascape.html#gal_post_55564_free-seascape-wallpaper-1.jpg

Brain exercising cartoon: http://tactustherapy.com/neuroplasticity-stroke-survivors/

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2016: The Year in Parkinson’s

“The most beautiful experience we can have is the mysterious. It is the fundamental emotion that stands at the cradle of true art and true science.” Albert Einstein

“Your assumptions are your windows on the world. Scrub them off every once in a while, or the light won’t come in.” Isaac Asimov

Summary: (Part 1) A brief review of my year with Parkinson’s. (Part 2) An overview of 12 scientific research studies on Parkinson’s from 2016.

Part 1. A personal Parkinson’s 2016 calendar review

Life with Parkinson’s: 706 days ago I started this blog ‘Journey with Parkinson’s’; and it’s been a remarkable journey through time since then.  Life is full, rarely a dull moment.  Dealing with a disorder like Parkinson’s is difficult because it slowly creeps around your body, somewhat stealth by nature but always ever present.  It requires a daily inventory of body movements, mental capacity and overall self-feelings compared to the day-week-month-year before.

Life is loving, fun, intellectually challenging, active, full, rarely a moment off; however, its best that way for me.  I close this paragraph by repeating two quotes from last year. They remind me to simply try to live as best as I am able for as long as I can.  My hope for you is likewise as well; keep going, keep working, stay active, stay the course.  Please make a manageable life-plan/contract with your care-partner, family and close friends; keep going, and please don’t give up.

“Never confuse a single defeat with a final defeat.” F. Scott Fitzgerald

“If you fell down yesterday, stand up today.” H.G. Wells

My year with Parkinson’s: To highlight my 2016, I’ve chosen 1 event/month to describe (not mentioned are the trips to the beach/vacation with Barbara, golf with the golf buddies, and other activities related to education, research and outreach for Parkinson’s.)  I am a very fortunate person.

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January-June, 2016:
(JAN) The 22nd year/class of undergraduates taking my spring semester course on ‘Biology of Blood Diseases’, great fun!
(FEB) An anniversary dinner with Barbara, a most loving person and the best care-partner.
(MAR) Started work on the WPC Parkinson Daily (eNewspaper) for the World Parkinson Congress).
(APR) Compiled all of the quotes from the students in class that led to the Kindle version (2016)/Paperback version (2017) of “A Parkinson’s Reading Companion”  (Click here to read about it).
(May) Graduation ceremonies are always on Mother’s Day weekend; it is filled with joy and regalia, promise and the future ahead for all of the graduates (typically, I attend the medical school ceremony on Saturday and as many undergraduate ceremonies on SAT-SUN my schedule permits (picture above is from the Dept. Biology commencement).
(JUN) A weekend in the Smoky Mountains in Asheville, NC: to attend a Parkinson’s retreat, to relax-renew-play golf, and to get a second Parkinson’s-related tattoo.

“Be happy for this moment. This moment is your life.” Omar Khayyam

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July-December, 2016:
(JUL) A weekend in Greenville, SC to participate and get certified in PWR! (Parkinson Wellness Recovery); an amazing experience (click here to read blog post about it).
(AUG) Truly a professional highlight of my career being chosen by the medical students to deliver the 2016 Richard H. Whitehead Lecture (click here to read blog post about it).
(SEP) Attended and presented a poster at the 4th World Parkinson Congress (WPC) in Portland, OR (click here to read about the WPC).
(OCT) Moving Day® NC Triangle, National Parkinson Foundation; great team and such a fun day/experience (click here to read about NC Triangle Moving Day).
(NOV) Research proposal submitted on the role of proteases and their inhibitors, alpha-synuclein and exercise in Parkinson’s. It is something I’ve been thinking about all of last year (click here to read about the funding program).
(DEC) Finished teaching the 3rd class of the Honor’s-version and fall semester of the undergraduate ‘Biology of Blood Diseases’ course; a great honor for me.

“Success is not the key to happiness. Happiness is the key to success. If you love what you are doing, you will be successful.” Albert Schweitzer

Part 2. The year (2016) in Parkinson’s science

Parkinson’s with a hopeful future: To live successfully with a chronic and progressing neurodegenerative disorder like Parkinson’s requires much, but in the least it takes hope.  We must remain hopeful that advances in Parkinson’s treatment are being made and that our understanding of the science of Parkinson’s is continuing to evolve.

Parkinson’s research: Parkinson’s is the most prevalent neurodegenerative movement disorder.  According to PubMed, there were 6,782 publications in 2016 that used “Parkinson’s disease” in the Title/Abstract.  Likewise in 2016, PubMed had 9,869 and 1,711 citations on Alzheimer’s disease and on Amyotrophic Lateral Sclerosis (ALS), respectively. Most research studies move in incremental steps; we describe a hypothesis and collect the data to hopefully advance us forward.

2016, the year in Parkinson’s: To remind us of some of these forward steps in Parkinson’s research, and to add to our base-level of hope, here are 12 projects from 2016 regarding Parkinson’s (there are several studies, not mentioned here, that I’m currently working on for individual blog posts because they seemed super-relevant and in need of more thorough presentation/explanation).  Although 12 is a minuscule list of citations/work reported from last year, it reinforces a simple notion that our trajectory is both positive and hopeful.

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January, 2016: Dipraglurant FDA-approved to treat dyskinesia. After ~5 years of treatment with the ‘gold-standard’ Levodopa/Carbidopa, many people-with-Parkinson’s develop drug-induced involuntary movement (also called dyskinesia).  This can be a serious side-effect of levodopa, and it can lead to numerous detrimental consequences.  The pharmaceutical company, Addex Therapeutics, has received orphan drug status for their drug named Dipraglurant, which will be used for the treatment of levodopa-induced dyskinesia.  Click here to read about the putative molecular mechanism of Dipraglurant, what advantages Addex gains from the designated orphan-drug status, and for more information about Addex.

“January is here, with eyes that keenly glow, A frost-mailed warrior striding a shadowy steed of snow.” Edgar Fawcett

February, 2016: Early detection of Parkinson’s from mouth salivary gland biopsy.   There is no definitive test to identify Parkinson’s in its early stages.  Finding an easily accessible tissue for  biopsy  to help with the diagnosis would be of value.  From autopsy samples, the submandibular saliva glands in the mouth seemed to be a relevant and easily accessible site to study.  The test involved inserting a needle into the submandibular salivary gland under the jaw,  staining for modified-a-synuclein.   The results revealed  that Parkinson’s patients had  increased level of a-synuclein  compared to patients  without Parkinson’s.  Click here to view this paper: Adler, Charles H. et al. “Peripheral Synucleinopathy in Early Parkinson’s Disease: Submandibular Gland Needle Biopsy Findings.” Movement disorders : official journal of the Movement Disorder Society 31.2 (2016): 250–256. PMC. Web. 13 Feb. 2017.

“Even though February was the shortest month of the year, sometimes it seemed like the longest.” Lorraine Snelling

March, 2016:  Three-dimensional scaffold used  to grow neuronal cells for transplant to brain.  Scientists have been able to convert adult stem cells into neuronal cells by culturing the stem cells in three-dimensional  scaffolding.   There are many obstacles successfully using stem cells to treat Parkinson’s disease; one of them is converting the stem cells into dopamine-producing-neuronal cells to replace the dead brain cells of the patient.   The three-dimensional scaffolding facilitated which allowed the neuronal cells to be injected into mice. Hopefully, this approach will eventually be ready for testing in humans; however, this is a potential glimpse to the future. To read this research paper, click here: “Generation and transplantation of reprogrammed human neurons in the brain using 3D microtopographic scaffolds” by Aaron L. Carlson et al., in Nature Communications. Published online March 17 2016 doi:10.1038/ncomms10862

“It was one of those March days when the sun shines hot and the wind blows cold: when it is summer in the light, and winter in the shade.” Charles Dickens, Great Expectations

April, 2016: Role of Mer and Axl in immune clearance of neurons in Parkinson’s.
TAM receptors are found on immune system cells and they help clear out dead cells  generated by out bodies.  Two of the TAM receptors, dubbed Mer and Axl, help immune cells called macrophages act as garbage collectors. This study asked whether or not the brain microglial cells (brain macrophages) had such activity through Mer and Axl.  Interestingly, in mice lacking Mer and Axl, neurons regenerated much more rapidly in certain areas of the brain. Furthermore, microglial expression of Axl was upregulated in the inflammatory environment in a mouse model of Parkinson’s.  These results identify TAM receptors as controllers of microglial scavenger activity and also as potential therapeutic targets for Parkinson’s.  Click here to view this article: Fourgeaud, L., et al. (2016). “TAM receptors regulate multiple features of microglial physiology.” Nature 532(7598): 240-244.

“April hath put a spirit of youth in everything. (Sonnet XCVIII)”  William Shakespeare, Shakespeare’s Sonnets

May, 2016:  Complex genetics found in the study of Parkinson’s in human brain tissue.  Genetic changes were found in Parkinson’s disease and Parkinson’s disease dementia.  A team of scientists used RNA sequencing to illuminate two phenomena linked with the onset of Parkinson’s disease: specifically, differential gene expression and alternative splicing of genes. The study describes 20 differentially expressed genes in Parkinson’s and Parkinson’s dementia, comparing these with healthy controls. Genes showing over-expression included those involved with cell movement, receptor binding, cell signaling and ion homeostasis. Under-expressed genes had an involvement with hormone signaling.  These results increase our understanding of Parkinson’s; furthermore, the complexity of their results suggest we may be able to achieve a more detailed diagnosis .  Click here to view paper: Henderson-Smith, Adrienne et al. “Next-Generation Profiling to Identify the Molecular Etiology of Parkinson Dementia.” Neurology: Genetics 2.3 (2016): e75.

“May, more than any other month of the year, wants us to feel most alive.” Fennel Hudson

June, 2016: Mutations in a gene called TMEM230 causes Parkinson’s. The role of TMEM230  was found to be in packaging the neurotransmitter dopamine in neurons.  Interestingly, TMEM230 bridges membranes in synaptic vesicles; these vesicles are storage reservoirs for neurotransmitters. Since the loss of dopamine-producing neurons defines Parkinson’s, a defect in TMEM230 implies a new link to a genetic cause of Parkinson’s.  The research team identified this mutation in Parkinson’s patients in North America and Asia. Click here to view paper: Deng, H-X, et al., “Identification of TMEM230 mutations in familial Parkinson’s disease”. Nature Genetics 48, 733–739 (2016).

“I wonder what it would be like to live in a world where it was always June.”  L.M. Montgomery

July, 2016: Improving deep brain stimulation (DBS), one patient at a time.  Instead of one-size-fits-all, these researchers are pioneering a novel strategy for fine-tuning DBS on each person’s individual physiology.  Their DBS platform, termed Phasic Burst Stimulation, has the potential to (i) enhance therapeutic efficacy, (ii) extend battery lifespan; (iii) reduce detrimental side effects, and (iv)  adjust as each person’s motor symptoms change.  This tuning-based DBS approach has real promise.  Click here to view paper: “Phasic Burst Stimulation: A Closed-Loop Approach to Tuning Deep Brain Stimulation Parameters for Parkinson’s Disease.” by A.B. Holt et al., PLOS Computational Biology, http://dx.doi.org/10.1371/journal.pcbi.100501

“My life, I realize suddenly, is July. Childhood is June, and old age is August, but here it is, July, and my life, this year, is July inside of July.” Rick Bass

August, 2016: Comparison of different movement disorders to better understand Parkinson’s.  These researchers compared multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) to Parkinson’s.  MSA and PSP are progressive disorders that also cause changes in balance and walking.  The study consisted of  functional magnetic resonance imaging (fMRI) brain scans with each person using a grip strength exercise, which showed changes in the regions of brain that control muscle movement. Parkinson’s patients showed changes in the putamen and the primary motor cortex;  MSA patients had changes in the primary motor cortex, the supplementary motor area and the superior cerebellum. PSP patients showed a change in all four areas.  Normal healthy controls had no changes. These detailed results (i) show the progression of each movement disorder and (ii) indicate that biomarkers for these specific-regions of the brain might be useful for not only monitoring disease progression but also response to therapy. Click here to view article: Burciu et al., “Functional MRI of disease progression in Parkinson disease and atypical parkinsonian syndromes.”, Burciu, Chung, Shukla, Ofori, McFarland, Okun, Vaillancourt, Neurology, 016 Aug 16;87(7):709-17. doi: 10.1212/WNL.0000000000002985

“The month of August had turned into a griddle where the days just lay there and sizzled.” Sue Monk Kidd, The Secret Life of Bees

September, 2016: Preventing falls by combining virtual reality and treadmill training.   Falling down is one of the most common and most detrimental problems in the elderly  with Parkinson’s. This research team combined treadmill use with virtual reality training. They tested a large group of older adults at high risk for falls; they found that treadmill training with virtual reality led to reduced fall rates compared to treadmill training alone.Click here to view article: Mirelman et al.,  “Addition of a non-immersive virtual reality component to treadmill training to reduce fall risk in older adults (V-TIME): a randomised controlled trial”, The Lancet, 2016 Sep 17;388(10050):1170-82. doi: 10.1016/S0140-6736(16)31325-3

“By all these lovely tokens September days are here, With summer’s best of weather And autumn’s best of cheer.”  Helen Hunt Jackson

October, 2016: Caffeine-based compounds stop alpha (a)-synuclein misfolding in a yeast model of Parkinson’s. The aggregation (misfolding) of the protein a-synuclein is thought to be a key contributing factor in neuronal cell death that leads to Parkinson’s.  The misfolded a-synuclein ultimately forms what are termed Lewy bodies, which produce much neuronal cell morbidity and mortality. Caffeine has been shown to be  somewhat protective against Parkinson’s. The study here made double-headed constructs of compounds using caffeine and nicotine and other chemicals and asked whether or not they could stop a-synuclein misfolding.  Possibly a far-fetched  idea, 2 of the caffeine-double-headed compounds worked.  These studies used a novel a-synuclein-fluorescent-green substance expressed in yeast.  Expression of the green-a-synuclein misfolded and killed the yeast; however, in the presence of the caffeine-adducts, the green-a-synuclein folded properly and the yeast stayed alive.  Such cool science.  To read this paper, click here) “Novel dimer compounds that bind α-synuclein can rescue cell growth in a yeast model overexpressing α-synuclein. a possible prevention strategy for Parkinson’s disease”, Jeremy Lee et al., ACS Chem Neurosci. Epub 2016 Oct 7. 2016 Dec 21;7(12):1671-1680. doi: 10.1021/acschemneuro.6b00209.

“Autumn is my favourite season of all. It is a transitory period that allows the earth to rest before it sees the harshness of winter and hears the promise of spring.”  Kamand Kojouri

November, 2016: PINK1 gene mutation linked to early onset of Parkinson’s.  A single mutation in the PTEN-induced putative kinase 1 (PINK1) gene has been found to promote  the development of early-onset Parkinson’s. There is growing evidence that PINK1 collaborates with the protein named PARKIN; together they help regulate neuronal cell mitochondria. This interaction to regulate mitochondria (the cell’s power plant) by  PINK1 and PARKIN is important because many brain disorders are known to have issues with energy production (mitochondria) besides Parkinson’s. Click here to view paper: Puschmann, A., et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain 2016; 140 (1): 98-117. doi: 10.1093/brain/aww261.

“October extinguished itself in a rush of howling winds and driving rain and November arrived, cold as frozen iron, with hard frosts every morning and icy drafts that bit at exposed hands and faces.”  J.K. Rowling, Harry Potter and the Order of the Phoenix

December, 2016:  President Obama signed the 21st Century Cures Act. Not a paper but a National Institute of Health (NIH) federally-supported research initiative. The Cures Act is focused on  cancer, brain disease, drug addiction and other diseases/processes for the next  decade. The 21st Century Cures Act contains $4.8 billion in new NIH (National Institutes of Health) funds, including the BRAIN Initiative for the comprehensive mapping of  the brain.  It is anticipated that we will achieve an even better understanding of Parkinson’s than we have today.  Recently, a commentary about the Cures Act from the viewpoint of the NIH was published in the New England Journal of Medicine. Click here to read this article: Hudson, K. L. and F. S. Collins (2017). “The 21st Century Cures Act — A View from the NIH.” New England Journal of Medicine 376(2): 111-113.

“December’s wintery breath is already clouding the pond, frosting the pane, obscuring summer’s memory…” John Geddes

“I like the scientific spirit—the holding off, the being sure but not too sure, the willingness to surrender ideas when the evidence is against them: this is ultimately fine—it always keeps the way beyond open—always gives life, thought, affection, the whole man, a chance to try over again after a mistake—after a wrong guess.”  Walt Whitman, Walt Whitman’s Camden Conversations

Useful Parkinson’s disease News/Health Information/Reference Sites (click on links below):
Google Scholar- Parkinson’s disease
Parkinson’s News Today Weekly Digest
Medical News Today (MNT)
Science News- Mind & Brain News
Harvard Medical School- Harvard Healthbeat
The Science of Parkinson’s disease
STAT
NY Times- Well
Neurology Advisor

Cover photo credit: winter smoky mts- http://holicoffee.com/wp-content/uploads/2015/05/great-smoky-mountains-national-park-usa-extreme-out-door-hiking-trail-adventure-37.jpg

PD word cloud- http://us.123rf.com/450wm/lculig/lculig1612/lculig161200292/66735623-parkinson-disease-word-cloud.jpg?ver=6

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Help with the Parkinson’s Tremor

“The starting point of all achievement is desire.” Napoleon Hill

“We can’t help everyone, but everyone can help someone.” Ronald Reagan

The Journey With Parkinson’s returns:  The past 2 months have just consumed every waking moment of my time/life, and then some.  I have a back-log of >20 blog posts in some finished-form-or-another. Starting this weekend, I will be able to spend more time researching, thinking, and writing on the blog (and the past 2 month gap between blog posts will be explained in a story entitled “Work in the Presence of Parkinson’s”).

Core movement disorder aspects of Parkinson’s: Most people-with-Parkinson’s have some or most of these manifestations: tremor, bradykinesia, postural instability and rigidity. They are considered the “Cardinal Signs” of Parkinson’s; here is a brief overview.

Resting Tremor: A vast majority of people-with-Parkinson’s will have this ‘type’ of tremor (for a tremor tutorial click here). The tremor consists of a shaking motion, which happens at rest. The affected body part will be in motion when it is not performing an action. The tremor will stop when a person moves this body part. Not all people with Parkinson’s will develop a tremor; or like me, they have another kind of tremor.

Bradykinesia (“slow movement”): A general loss of spontaneous body movement. Bradykinesia causes problems with repetitive motion. Bradykinesia can alter the speed of performance of many everyday events like buttoning shirt-buttons, fastening car seatbelt, or chopping food.

Postural Instability: Postural instability is a tendency to be unstable when standing upright. A person with postural instability has lost some of the reflexes needed for maintaining an upright position.

Rigidity: Rigidity causes stiffness and inflexibility of the limbs, neck and trunk. Muscles normally stretch when they move, and then relax when they are at rest.  By contrast, in Parkinson’s that body part remains taut when it moves and does not relax.

Smart-spoon: The “Google Spoon” came first (click here), and it oscillates to counter the negative oscillation of your hand (click here).  You can check on-line to determine whether or not your tremor can be helped by this spoon.

And now a helping hand:  “The invention that helped me write again” (Click here to see video).  My colleague, good friend and golf buddy Nigel saw the story on BBC News.  Technology is evolving; all it takes is an understanding of the problem, a design strategy, and significant effort to create such a device.  It also takes intelligence, talent and diligence to be able to make a device that allowed someone with Parkinson’s and a significant tremor to be able to write and draw again.  Great story, and simply an amazing device!

“The trouble with much of the advice business gets today about the need to be more vigorously creative is that its advocates often fail to distinguish between creativity and innovation. Creativity is thinking up new things. Innovation is doing new things… The shortage is of innovators…” Tom Peters

Cover photo credit: http://vb3lk7eb4t.search.serialssolutions.com/?V=1.0&L=VB3LK7EB4T&S=JCs&C=TC0001578421&T=marc

The 23andMe Parkinson’s Research Study

“Somewhere, something incredible is waiting to be known.” Carl Sagan

“A dream doesn’t become reality through magic; it takes sweat, determination and hard work.” Colin Powell

Introduction/Background: Parkinson’s disease is a neurodegenerative disorder that affects movement. It evolves slowly, usually starting as either stiffness in a hand or a small tremor. Over time, Parkinson’s progresses; typically characterized by motor symptoms such as slowness of movement (bradykinesia) with rigidity, resting tremor (Parkinsonian tremor), balance and walking problems, and difficulty swallowing and talking. Parkinson’s has several non-motor symptoms including anxiety, depression, insomnia  and psychosis (just to mention a few). ~60,000 new cases of Parkinson’s disease are diagnosed each year in the United States, adding to the greater than one million people who currently have Parkinson’s.  It has been estimated that 7-10 million people worldwide are living with Parkinson’s.

“Enclose your heart in times of need with the steel of your determination and your strength. In doing this, all things will be bearable.” Lora Leigh

Genetic Testing and Introduction/Background to 23andMe:
What is the “Central Dogma of Life”? (click here) The process of how the information and instructions found in DNA to become a functional protein is termed the ‘Central Dogma’.  The concept of the central dogma was first proposed in 1958 by Francis Crick, one of the discoverers of the structure of DNA. The central dogma states that the pattern of information that occurs most frequently in our cells is as follows: (i) use existing DNA to make new DNA  (replication); (ii) next, from DNA to make new RNA (transcription); and (iii) finally, using RNA to synthesize new protein (translation). The drawing below depicts the central dogma (the drawing is from this video, click here).


23andMe: What does the name 23andMe represent? Our genetic material  (genes) are housed in chromosomes and they are composed of DNA. We have 23 pairs of chromosomes in each cell capable of producing new proteins; thus, the name of the company makes sense.  23andMe provides DNA testing services.  The information derived from studying your DNA and genetic make-up can provide information about your ancestry, your genetic predisposition to many different diseases, drug responses and inherited conditions.

16.07.21.3.

“When burned on a CD, the human genome is smaller than Microsoft Office.” Steve Jurvetson

There’s an old saying that goes “Mother is always right.”:  My mother said for her entire life that we were English, Scottish (or Irish), French and German in our ancestral ‘gene pool’.  Several years ago, my extended family and I took to spitting into the 23andMe test-tubes.  We mailed them back to the company to establish our genetic history and screen our family gene pool for several diseases and their inherited susceptibility. Guess what?  Mom was absolutely right about our family ancestry.  Interestingly, there was no evidence of early onset Parkinson’s in my extended family; thus, my disorder is the sporadic/idiopathic type of Parkinson’s.

“A mother’s love for her child is like nothing else in the world. It knows no law, no pity, it dares all things and crushes down remorselessly all that stands in its path.” Agatha Christie

The 23andMe Parkinson’s research study: A few years ago, 23andMe decided to better understand the genetics of Parkinson’s disease; thus, the Parkinson’s research initiative.  Their goal is as follows: to understand the genetic associations found between Parkinson’s patients’ DNA and our disease; to take this new knowledge and search for a cure; and ultimately, they strive to enhance and speed-up how Parkinson’s disease is studied to better understand the genetics of the disease (click here to read further details) It’s easy to get involved in the 23andMe Parkinson’s research study, here are the eligibility requirements: (1) You have been diagnosed with Parkinson’s disease by a qualified physician; (2) You are willing to submit a saliva sample for DNA testing and complete online surveys related to your condition; (3) You have access to the internet; and (4) You are at least 18 years old.  The flow-chart below shows all one has to do to join this community of people-with-Parkinson’s helping out to search for a cure.
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23andMe has an impressive group of  primary research partners and several other organizations as supporting partners, see below. To date, more than 10,000 people have agreed to be in 23andMe’s Parkinson’s Research Community, which makes it the world’s largest collective of genotyped Parkinson’s patients. Furthermore, many thousands of people without Parkinson’s have also consented to participate in these research studies.

16.07.21.2 “Research is to see what everybody else has seen, and to think what nobody else has thought.” Albert Szent-Gyorgyi

It’s a personal decision and choice, but it’s also advancing our knowledge of Parkinson’s:  If you have concerns, look over the 3 websites cited below.  The question is should you volunteer your DNA for the study?  Should you consent to have your DNA further sequenced?  And the nice thing about being involved is you don’t have to leave your home to participate; it’s an in-house study in that they mail you the tube/device, you spit into it, and mail it back to 23andMe.  Simple. Valuable. Straightforward. Elegant.  Contributing. Joining the Parkinson’s team.

7 Things You Should Know About The Future Of Your Genetic Data (click here)
23andMe DNA Test Review: It’s Right For Me But Is It Right for You? (click here)
DNATestingChoice.com (click here for a review of 23andMe)

Ponder it, think about it some more, possibly fill out the questionnaire, upload the information, you are now part of the Parkinson’s 23andMe team. Why should you participate? You will be providing your own small piece to the Parkinson’s genetic puzzle; help complete the assembly of the landscape to this amazing puzzle.

You will matter whether you participate or not; you will always matter.  However, congratulate yourself if you decide to join the team; the 23andMe Parkinson’s research study.  You can be part of the unraveling and the delineation of the genetic anomalies that cause Parkinson’s.

“It is ironic that in the same year we celebrate the 50th anniversary of the discovery of DNA, some would have us ban certain forms of DNA medical research. Restricting medical research has very real human consequences, measured in loss of life and tremendous suffering for patients and their families.” Michael J. Fox

Cover photo credit: http://www.hdwallpapersact.com/wp-content/uploads/2013/04/ summer-sunset-on-beach-hd.jpg

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Treatment of Parkinson’s Psychosis with Nuplazid

“At what point do you give up – decide enough is enough? There is only one answer really. Never.” Tabitha Suzuma

“Be proud of your scars. They remind you that you have the will to live.” Paulo Coelho

Précis: ~50% of the people with Parkinson’s develop psychotic tendencies. Treatment of their psychosis can be relatively difficult. However, a new drug named Nuplazid™ was just approved by the FDA specifically designed to treat Parkinson’s psychosis. A brief review follows.

Psychosis in Parkinson’s (Hallucinations and Delusions): Psychosis can occur in ~50% of Parkinson’s patients. The Parkinson’s psychosis typically results in hallucinations (where you see or hear things that are not there) and/or delusions (where you have false beliefs). As one could imagine, hallucinations and delusions would be severe/serious aspects of this disorder.  Parkinson’s psychosis requires treatment because these symptoms are life-altering; they lead to an imbalanced emotional status, and they would disrupt interactions with loved ones and others.

“Severe mental illness like psychosis can lead to a tragedy like this – that people can see things that aren’t real and hear things that aren’t real and believe things that aren’t real, and act in that distorted reality.” Andrea Yates

Antipsychotic Drugs (APD) Typically Target Dopamine Receptors: There are many antipsychotic (neuroleptic) drugs available. Historically, most of these drugs target neurotransmitters that regulate nerve cell communications. Blocking the neurotransmitter dopamine is thought important to managing symptoms of psychosis. Modern pharmacology has not only expanded the drugs available, but many years of research has expanded the ‘targets’ for antipsychotic drugs (ADP).

The usual targets for most APD’s include dopamine receptors, serotonin receptors and other monoamine receptors (see figure below).  Therefore, if you are being treated for both Parkinson’s disease and Parkinson’s psychosis you can immediately see the ‘problem’. You likely take some form/mimic of dopamine to manage the movement disorder; at the same time, you could be blocking dopamine receptors with an APD being used to manage the Parkinson’s psychosis. This would likely create an antagonistic medication/treatment-relationship in managing the disorder.

16.06.05.Nuplazid


“He wrote on a piece of paper with his pencil. Psychosis: out of touch with reality. Since then, I have been trying to find out what reality is, so that I can touch it.” Jeanette Winterson

“New-Kid-on-the-Block” (Nuplazid™) to Treat Parkinson’s Psychosis: The US FDA has approved Nuplazid (pimavanserin), the first APD of its kind to treat the hallucinations and delusions associated with Parkinson’s psychosis. Nuplazid is being marketed by Acadia Pharmaceuticals Inc. of San Diego, California (click here for more detailed information about Nuplazid). Nuplazid was given breakthrough therapy designation and priority review by the FDA (click here to read the FDA news release); the goal was to help relieve symptoms in Parkinson’s psychosis.

Unlike other APD’s that have broader target sites, as depicted in the figure above, Nuplazid is a selective inverse agonist that targets 5-HT2 serotonin receptors. What is an ‘inverse agonist’?  A slight diversion into pharmacology says that “an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist.” (click here to read more). For a visual depiction on how an inverse agonist works as a drug, see the drawing below.

Inverse_agonist_3.svg

Nuplazid Offers New Hope: Using Nuplazid to treat Parkinson’s psychosis should have no negative impact on motor symptoms that need treatment in Parkinson’s. Michael S. Okun, MD, Medical Director of The National Parkinson Foundation, said last month: “Today’s approval of Nuplazid represents a major paradigm shift in the treatment of Parkinson’s disease psychosis. Through its novel and selective mechanism of action, Nuplazid is a breakthrough treatment that works in a whole new way— treating hallucinations and delusions without blocking dopamine receptors and, therefore, not impairing motor function in Parkinson’s psychosis patients.”  Thus, Nuplazid is both a first step and a new approach for managing the symptoms of Parkinson’s psychosis. Only time will tell if Nuplazid is a hopeful beginning for treating Parkinson’s psychosis.

“If we want to cultivate hopefulness, we have to be willing to be flexible and demonstrate perseverance. Not every goal will look and feel the same. Tolerance for disappointment, determination, and a belief in self are the heart of hope.” Brené Brown

Cover image credit: http://www.fyiaonly.com/wp-content/uploads/2014/06/Great-Smoky-Mountains.jpg

Inverse agonist figure credit: https://upload.wikimedia.org/wikipedia/commons/6/6c/Inverse_agonist_3.svg

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Part 1: Journey to Parkinson’s and Barium Swallow

“It does not do to dwell on dreams and forget to live.” J.K. Rowling, Harry Potter and the Sorcerer’s Stone

“May you live every day of your life.” Jonathan Swift

 Introduction: Along the way to the diagnosis of Parkinson’s, you may have to undergo several different kinds of tests to help your physician(s) learn what actually is going on with your physiology and neurological network.  Remember there is neither a blood test nor a genetic marker evaluation to provide a diagnosis of Parkinson’s. Therefore, the clinical exams I will describe are sometimes done to exclude other disorders and to further implicate Parkinson’s.  My Neurologist says the most helpful thing is the actual patient interview (History and Physical) since most people with Parkinson’s have a characteristic set of signs and symptoms.

These posts (a series of 5 procedures) are purely descriptive/informational but they are important to describe because they can be kind of intimidating and nerve-racking  to undergo (just in case any of these tests are suggested by your physician team).  Let me be clear, I am not recommending any of these procedures for you (I’m a basic scientist not a physician). Interestingly, my Neurologist was involved only in the MRI and sleep study, which were done after my diagnosis of Parkinson’s. The other procedures were done before my diagnosis as we (another group of very talented physicians) were trying to sort out what was wrong. These are the procedures:
Part 1 describes the Barium Swallow test;
Part 2 gives an overview of Magnetic Resonance Imaging (MRI);
Part 3 highlights Polysomnography, which is a sleep study;
Part 4 presents Electromyography (EMG), which measures nerve/muscle interactions;
Part 5 characterizes Transradial Cardiac Catheterization and Angiography.

What causes someone to have difficulty in swallowing (dysphagia)? Dysphagia is the medical term used to describe someone with difficulty or discomfort from swallowing;  it is harder or takes longer to get food, liquid or pills from your mouth to your stomach. Dysphagia usually means something is not working properly in your mouth, pharynx or esophagus. Dysphagia typically occurs in older adults, and in people with brain or nerve injuries or disease.  There are two broad pathological categories  that cause dysphagia: disorders that affect the nerves and muscles of the throat and esophagus; and disorders that interfere/ block the throat and esophagus. WebMD has a very nice overview of the many causes of dysphagia (please click here).

“I may not have gone where I intended to go, but I think I have ended up where I needed to be.” Douglas Adams, The Long Dark Tea-Time of the Soul

What is a barium swallow study? How does a barium swallow study work?  Barium swallow remains the primary clinical evaluation of dysphagia.  Like the more  familiar  substance calcium, barium is also an alkaline earth metal  with a +2 charge.  When the compound barium sulfate is dissolved in water, it forms a thick chalky paste that absorbs X-rays, which is the basis of the barium swallow study. A barium swallow uses X-rays (radiographic) to examine the pharynx (back of mouth and throat) and the esophagus (a hollow tube that connects the back of the mouth to the stomach). Barium coats the lining of the pharynx and esophagus to make them visible when exposed to X-rays (electromagnetic energy that is used to visualize various internal organs). The combination of barium/ X-ray gives the radiologist a ‘movie’ (Fluoroscopy) to watch the movement of barium through the upper gastrointestinal tract.

BariumSwallow
The left panel above shows the orientation of the pharynx and esophagus between the back of the mouth and stomach, respectively; and in the middle and right panels show the result of a normal barium swallow study in a static X-ray.

For the procedure, you will be both horizontal and vertical on an imaging platform with the other body parts shielded and protected from the X-rays. You will be asked to drink a barium solution with the consistency of a milkshake. Barium actually has very little flavor. Additionally, I was given barium pills to simulate pill ingestion. Furthermore, I was also given barium mixed into applesauce and barium coated on top of graham crackers to simulate different types of textured food while you chew and swallow.  The coolest thing is you actually get to see the results in real time as you  swallow the various forms of barium. Besides the radiology people, I also had a speech pathologist present who specialized in  dysphagia.   The only difficulty in dealing with the barium swallow study was the constipation that occurred from ingestion of barium. For a more comprehensive overview of the barium swallow study (please click here) and see references cited at the bottom.

330px-Normal_barium_swallow_animation-1
The image above is a barium (solution) swallow study and the resulting x-ray ‘movie’.

“It may be unfair, but what happens in a few days, sometimes even a single day, can change the course of a whole lifetime…” Khaled Hosseini ,The Kite Runner

What is the relationship of dysphagia to Parkinson’s?  One of the earliest presenting features of my Parkinson’s was a swallowing defect, which occurred several years before my diagnosis. Interestingly, dysphagia can occur at any stage of Parkinson’s. Signs and symptoms  of a swallowing problem go from mild to severe and  typically present as follows: coughing/throat clearing  while eating/drinking; trouble swallowing certain foods or liquids; and  having a feeling  that food is getting stuck  in the back of your throat. Anyone with a swallowing defect clearly needs to be seen by a speech pathologist and your neurologist,  which would likely include a barium swallow study.

“Life is like riding a bicycle. To keep your balance, you must keep moving.” Albert Einstein

Useful reference material: there is a lot of material on the Internet to read regarding dysphagia,  barium swallow, and  dysphagia in Parkinson’s. However,  I found the following to be very useful in learning about swallowing defects in Parkinson’s:
-Barium Swallow  (from the University of Rochester Medical Center describing all the aspects of barium swallow, to view it click here);
-Dysphagia (from WebMD with a nice overview of dysphagia, please click here).
-Upper Gastrointestinal Examination [from the Lahey Clinic in Boston with a very nice overview (text/visual) of the upper GI exam, to view it click here];
Parkinson Disease: Speech and Swallowing (from the National Parkinson Foundation, an informative and well-written pamphlet);
-Swallowing and Parkinson’s Disease  (from the U.S. Veterans Administration, an  interesting presentation describing dysphagia in  Parkinson’s, to view it click here).

“I wanted a perfect ending. Now I’ve learned, the hard way, that some poems don’t rhyme, and some stories don’t have a clear beginning, middle, and end. Life is about not knowing, having to change, taking the moment and making the best of it, without knowing what’s going to happen next. Delicious Ambiguity.” Gilda Radner

Cover photo credit: http://www.pachd.com/free-images/napa/napa-07.jpg
Pharynx and esophagus d: https://sites.google.com/a/mtlstudents.net/wallace-davis-digestive/_/rsrc/1429639718932/home/pharynx-and-esophagus/normal-pharynx-esophagus-anatomy-lg-bdy.jpg?height=320&width=200
Normal barium swallow X-ray image: http://images.radiopaedia.org/images/501264/edcd492f95768c4dcd045283fe7845.jpeg
Barium swallow gif-movie: By Normaler_Schluck-00.jpg (and others): Hellerhoffderivative work: Anka Friedrich (talk) – 34 files:Normaler_Schluck-00.jpg[…]Normaler_Schluck-33.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15333554

 

 

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