Category Archives: Research

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


 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.


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.

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.



“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.

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Parkinson’s Disease Research: A Commentary from the Stands and the Playing Field

“You can have a very bad end with Parkinson’s, but on the other hand, you can be like me, because I’m lucky. I’m not having a bad end.” Margo MacDonald

“My age makes me think how valuable life is. How bad is something like Parkinson’s in relation to not having life at all?” Michael J. Fox

Introduction: Last month, together with Dr. Simon Stott and his team of scientists (The Science of Parkinson’s Disease), we co-published a historical timeline of Parkinson’s disease beginning with the description of the ‘shaking palsy’ from James Parkinson in 1817. My post entitled “Milestones in Parkinson’s Disease Research and Discovery” can be read here (click this link). The Science of Parkinson’s Disease post entitled “Milestones in Parkinson’s Disease Research and Discovery” can be read here (click this link).

We spent a lot of time compiling and describing what we felt were some of the most substantial findings during the past 200 years regarding Parkinson’s disease.  I learned a lot; truly amazing what has been accomplished in our understanding of  such a complex and unique disorder.  Simon posted a follow-up note entitled “Editorial: Putting 200 years into context” (click this link). I have decided to also post a commentary from the standpoint of (i) being someone with Parkinson’s and (ii) being a research scientist.

“Every strike brings me closer to the next home run.” Babe Ruth

Baseball: I want to use the analogy of a baseball game to help organize my commentary. Baseball fans sit in the stands and have fun watching the game, thinking about the strategy behind the game, eating/drinking, and sharing the experience with family/friends/colleagues.   Most baseball players begin playing early in life and the ultimate achievement would be to reach the major leagues. And this would usually have taken many years of advancing through different levels of experience on the part of the ballplayer. How does how this analogy work for me in this blog? Stands: I am a person-with-Parkinson’s watching the progress to treat and/or cure this disorder. Playing field: I am a research scientist in a medical school (click here to view my training/credentials).

“Never allow the fear of striking out keep you from playing the game!”  Babe Ruth

Observation from the stands:
I am a spectator like everyone else with Parkinson’s. I read much of the literature available online.  Like you, I think about my disorder; I think about how it’s affecting me every day of my life. Yes, I want a cure for this disease.  Yes, I’m rather impatient too.  I understand the angst and anxiety out there with many of the people with Parkinson’s. In reality, I would not be writing this blog if I didn’t have Parkinson’s. Therefore, I truly sense your frustration that you feel in the presence of Parkinson’s, I do understand.  Given below are examples of various organizations and ads and billboards in support of finding a cure for Parkinson’s.  Some even suggest that a cure must come soon.   However, the rest of my post is going to be dedicated to trying to explain why it’s taking so long; why I am optimistic and positive a cure and better treatment options are going to happen.  And it is partly based on the fact that there really are some amazing people working to cure Parkinson’s and to advance our understanding of this disorder.

“When you come to a fork in the road take it.” Yogi Berra

Observations from the playing field (NIH, war on cancer, research lab, and advancing to a cure for Parkinson’s):

National Institutes of Health (NIH) and biomedical research in the USA: Part of what you have to understand, in the United States at least, is that a large portion of biomedical research is funded by the NIH (and other federally-dependent organizations), which receives a budget from Congress (and the taxpayers). What does it mean for someone with Parkinson’s compared to someone with cancer or diabetes? The amount of federal funds committed to the many diseases studied by NIH-funded-researchers are partly divvied up by the number of people affected. I have prepared a table from the NIH giving the amount of money over the past few years for the top four neurodegenerative disorders, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), and Huntington’s Disease, respectively [taken from “Estimates of Funding for Various Research, Condition, and Disease Categories” (click here)]. And this is compared to cancer and coronary arterial disease and a few other major diseases. Without going into the private organizations that fund research, a large amount of money comes from the NIH. Unfortunately, from 2003-2015, the NIH lost >20% of its budget for funding research (due to budget cuts, sequestration, and inflationary losses; click here to read further).   Therefore,  it is not an overstatement to say getting  funded today by the NIH is fiercely competitive.  From 1986 to 2015, my lab group was supported by several NIH grants and fellowships  (and we also received funding from the American Heart Association and Komen for the Cure).


“In theory, there is no difference between theory and practice. But in practice, there is.” Yogi Berra

War against cancer: In 1971, Pres. Richard Nixon declared war against cancer and Congress passed the National Cancer Act.  This created a new national mandate “to support research and application of the results of research to reduce the incident, morbidity, and mortality from cancer.” Today, cancer is still the second leading cause of death in the USA; however, we’ve come such a long way to improving this statistic from when the Cancer Act was initiated.

Scientifically, in the 1970’s, we were just learning about oncogenes and the whole field of molecular biology was really in its infancy. We had not even started sequencing the human genome, or even of any organism.  We discovered genes that could either promote or suppress cellular growth.   We began to delineate the whole system of cell signaling and communications with both normal and malignant cells. We now know there are certain risk factors that allow us to identify people that may have increased risk for certain cancers. Importantly,  we came to realize that not all cancers were alike,  and it offered the notion to design treatment strategies for each individual cancer.  For example,  we now have very high cure rates for childhood acute leukemia and Hodgkin’s lymphoma and we have significantly improved survival statistics for women with breast cancer. Many might say this was a boondoggle and that we wasted billions of dollars  funding basic biomedical research on cancer; however, basic  biomedical research is expensive and translating that into clinical applications is even more expensive.  [ For a  very nice short review on cancer research please see the following article, it may be freely accessible by now: DeVita Jr, Vincent T., and Steven A. Rosenberg. “Two hundred years of cancer research.” New England Journal of Medicine 366.23 (2012): 2207-2214.]

“One of the beautiful things about baseball is that every once in a while you come into a situation where you want to, and where you have to, reach down and prove something.” Nolan Ryan

The biomedical research laboratory environment:  A typical laboratory group setting is depicted in the drawing below. The research lab usually consists of the lead scientist who has the idea to study a research topic, getting grants funded and in recruiting a lab group to fulfill the goals of the project.  Depending on the philosophy of the project leader the lab may resemble very much like the schematic below or may be altered to have primarily technicians or senior postdoctoral fellows working in the lab  (as two alternative formats). A big part of academic research laboratories is education and training the students and postdocs to go on to advance their own careers; then you replace the people that have left and you continue your own research.  Since forming my own lab group in 1986, I have helped train over 100 scientists in the research laboratory: 17 graduate students, 12 postdoctoral fellows, 17 medical students, and 64 undergraduates. The lab has been as large as 10 people and a small as it is currently is now with two people. People come to your lab group because they like what you’re doing scientifically and this is where they want to belong for their own further training and advancement.  This description is for an academic research  laboratory; and  I should also emphasize that many people get trained in federal government-supported organizations, private Pharma and other types of research environments that may differ in their laboratory structure and organizational format.


“Hitting is 50% above the shoulders.” Ted Williams

 In search of the cure for Parkinson’s:    First, I understand the situation you’re in with Parkinson’s because I’m living through the same situation.   But when people find out I’m a research scientist they always wonder why aren’t we doing more to find a cure, and I  hear the sighs of frustration and I see the anxiety in their faces. Second, the previous three sections are not meant to be an excuse for why there is still no cure for Parkinson’s. It is presented in the reality of what biomedical research scientists must undergo to study a topic.  Third, the experiments that take place in basic biomedical research laboratory may happen over weeks to months if successful. Taking that laboratory data to the clinic and further takes months and years to succeed if at all.   The section on cancer reminds me a lot of where we are going with Parkinson’s and trying to advance new paradigms in the treatment and curative strategies.  Professionally, I have even decided  to pursue research funding in the area of Parkinson’s disease.   Why not spend the rest of my academic career studying my own disease; in the least I can help educate others about this disorder. Furthermore, I can assure you from my reading and meeting people over the last couple of years, there are many hundreds of scientists and clinicians throughout this world studying Parkinson’s and trying to advance our understanding and derive a cure.  I see their devotion, I see their commitment to helping cure our disorder.

The science behind Parkinson’s is quite complicated. These complications suggest that Parkinson’s may be more of a syndrome rather than a disease. Instead of a one-size-fits-all like a disease would be classified; Parkinson’s as a syndrome would be a group of symptoms which consistently occur together.  What this might imply is that some treatment strategy might work remarkably well on some patients but have no effect on others. However, without a detailed understanding and advancement of what Parkinson’s really is we will never reach the stage where we can cure this disorder.

In a recent blog from the Science of Parkinson’s disease, Simon nicely summarized all the current research in 2017 in Parkinson’s disease (click here to read this post). To briefly summarize what he said is that there are multiple big Pharma collaborations occurring to study Parkinson’s.  There are more than 20 clinical trials currently being done in various stages of completion to prevent disease progression but also to try to cure the disorder.  From a search of the literature, there are literally hundreds of research projects going on that promise to advance our understanding of this disorder. With the last point, it still will take time to happen. Finally, I am a realist but I’m also optimistic and positive that we’re making incredible movement toward much better therapies, which will eventually lead to curative options for Parkinson’s.

And a final analogy to baseball and Parkinson’s, as Tommy Lasorda said “There are three types of baseball players: those who make it happen, those who watch it happen, and those who wonder what happens.”  I really want to be one of those scientists that help make it happen (or at least to help advance our understanding of the disorder).

“You can’t expect life to play fair with your heart or your brain or your health. That’s not the nature of the game we call life. You have to recognize the nature of the game and know that you can do your best to make the right choices, but life if going to do whatever the hell it pleases to you anyway. All you can control is how you react to whatever life throws at you. You can shut down or you can soar.” Holly Nicole Hoxter

Cover photo credit: PNC Park photo:

Sign post

Building Empathy for Parkinson’s

“When people talk, listen completely. Most people never listen.”  Ernest Hemingway

“To perceive is to suffer.”  Aristotle

Introduction: The loss of dopamine-producing neurons in the mid-brain leads to Parkinson’s disease, which usually presents with motor dysfunction of different degrees of progression from person-to-person.  This post explores the differences between empathy and sympathy, and describes a new device that allows one to actually experience a person-with-Parkinson’s tremor; surely providing much empathy from the experience.

“No one cares how much you know, until they know how much you care”  Theodore Roosevelt

A lesson learned from the classic rock opera “Tommy” by The Who: The plot of the 1969 rock opera “Tommy” begins with Tommy’s parents.  His father, Captain Walker, fought in World War II but it is assumed he died. However, Captain Walker is alive and returns home to his wife and Tommy. Believing her husband to be dead, Mrs. Walker has a new lover.  Captain Walker accidentally kills the lover, in the presence of Tommy. Tommy is traumatized by what he witnessed; he becomes catatonic.  Three musical examples: Go to the Mirror (listen here) Tommy sings “See me, me, feel me, touch me, heal me / See me, feel me, touch me, heal me.” Tommy’s father sings “I often wonder what he is feeling / Has he ever heard a word I’ve said? / Look at him in the mirror dreaming / What is happening in his head?” In Tommy Can You See Me? (listen here)  his mother sings “Tommy can you hear me? / Can you feel me near you? /  Tommy can you feel me / Can I help to cheer you.” In See Me, Feel Me (listen here) Tommy sings “See me, feel me, touch me, heal me / See me, feel me, touch me, heal me / See me, feel me, touch me, heal me / See me, feel me, touch me, heal me / Listening to you, I get the music / Gazing at you, I get the heat / Following you, I climb the mountain / I get excitement at your feet.” Hopefully, you can empathize, not sympathize, with Tommy and the life-struggles he encounters and overcomes in this rock opera.

“for there is nothing heavier than compassion. Not even one’s own pain weighs so heavy as the pain one feels with someone, for someone, a pain intensified by the imagination and prolonged by a hundred echoes.” Milan Kundera

*Empathy vs. sympathy: Empathy means you have the ability to understand and share the feelings of another.  By contrast, sympathy means feelings of pity and sorrow for someone else’s misfortune ( Yes, it sucks to have a chronically-progressing neurodegenerative disorder like Parkinson’s. But it could be worse, really.

Empathy.  What a great word.  Try to be empathetic to me; you don’t have to become one with me, just strive to understand how I’m feeling.  Our bond will surely strengthen.  You may not be able to exactly feel what I’m feeling, but just trying says much to you, your inner processing, the soul of your humanity.

Please don’t pity me, that reduces the feelings between us.  Please don’t have sorrow or sadness for me, it weakens our ties. If you give me sympathy, you’ll never truly be able to grasp the extent and meaning of my Parkinson’s.  Parkinson’s is not my friend; however, having your friendship and understanding (empathy) instead of your pity (sympathy) will give me strength and help me deal on a more positive-front with this unrelenting disorder.

*This post is dedicated to the first-year medical students at the UNC School of Medicine. On Friday, May 5, I had the privilege and honor of being presented as a person-with-Parkinson’s in our Neurologic Block. They asked very specific questions in their attempt to understand Parkinson’s and to learn how I am living with this disorder. It was clear that they were trying to follow the advice of Dr. William Osler who said “It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.”

“Some people think only intellect counts: knowing how to solve problems, knowing how to get by, knowing how to identify an advantage and seize it. But the functions of intellect are insufficient without courage, love, friendship, compassion, and empathy.”  Dean Koontz

What is the life expectancy of someone diagnosed with Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease? These neurodegenerative disorders are listed in ranked order of how many people are affected from most to least, respectively. Alzheimer’s typically progress over 2 to 20 years, and individuals live for 8 to 10 years after the diagnosis.  People who have Parkinson’s usually have the same average life expectancy as people without the disease.  Life expectancy from ALS is usually at least 3-4 years. The time from diagnosis  of Huntington’s to death is about 10 to 30 years.  Each of these disorders is uniquely different and unsettling to me; but your empathy, not your sympathy, will truly help me sail my boat along the shoreline for many more years.  Accept me with ‘my unique medical issues’, try to understand it. Your empathy will add stability to my battle; just watch.

“Resolve to be tender with the young, compassionate with the aged, sympathetic with the striving, and tolerant of the weak and the wrong. Sometime in life you will have been all of these.” Lloyd Shearer

A novel engineering device is empathy-producing to someone with Parkinson’s: The whole story is revealed from watching this video (click here). Klick Labs in Toronto, Canada, has created the SymPulse Tele-Empathy Device. This device is capable of mimicking and producing the tremors and involuntary movements of someone with Parkinson’s in people without Parkinson’s. The video is quite powerful, you immediately sense the empathy.

The SymPulse Tele-Empathy Device is based on digitized muscle activity from electromyograms of Parkinson’s patients. The signal is unique for each person with Parkinson’s. When the person without Parkinson’s receives this novel voltage pattern, their muscles will contract exactly as found in the person with Parkinson’s. Developing such a device shows the deviant nature of Parkinson’s to disrupt/distort normal neuro-muscular circuitry.

This device could be used to increase empathy in doctors and other caregivers. And it could enable family members and loved-ones the unique opportunity to experience the actual tremor/involuntary movements of their special person with Parkinson’s. Company officials note that most people wear the device for at most a couple of minutes; turn off the device and they return to normal. Remember, there is no off-on switch for the person with Parkinson’s.  I can only imagine empathy evolving from this device when used on someone without Parkinson’s.

“When we honestly ask ourselves which person in our lives mean the most to us, we often find that it is those who, instead of giving advice, solutions, or cures, have chosen rather to share our pain and touch our wounds with a warm and tender hand. The friend who can be silent with us in a moment of despair or confusion, who can stay with us in an hour of grief and bereavement, who can tolerate not knowing, not curing, not healing and face with us the reality of our powerlessness, that is a friend who cares.” Henri J.M. Nouwen

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“Go the Distance” With MAO-B Inhibitors: Potential Long-term Benefits in Parkinson’s

“Life is 10 percent what you make it, and 90 percent how you take it.” Irving Berlin

“My attitude is that if you push me towards something that you think is a weakness, then I will turn that perceived weakness into a strength.” Michael Jordan

Précis:  (1) A brief review of the major classes of therapeutic compounds for treating Parkinson’s. (2) Defining clinical trials.  (3) Hauser et al.(Journal of Parkinson’s Disease vol. 7, no. 1, pp. 117-127, 2017) report that Parkinson’s patients who received an MAO-B inhibitor for a long period of time had statistically significant slower decline in their symptoms compared to patients not on an MAO-B inhibitor (click here to see paper). (4) Addendum: “New Kid In Town”, The FDA approves another MAO-B inhibitor named Xadago (safinamide). 

Pharmacological treatment of Parkinson’s [Please note that these views and opinions expressed here are my own. Content presented here is not meant as medical advice. Definitely consult with your physician before taking any type of drug.]: The management of Parkinson’s is broadly divided up into motor and non-motor therapy.  A brief description of the therapy for motor dysfunction will be presented here.  Please see the drawing below for an overview.   Within the framework of treating someone with Parkinson’s you must consider managing their symptoms with the hope that some compound might possess either  neuroprotective or neurorestorative actions. To date, we do not have a cure for Parkinson’s but the study described below suggests an existing compound may be neuroprotective when used for a long  time.


“Things turn out best for the people who make the best of the way things turn out.” John Wooden

Medical management of the motor-related symptoms of Parkinson’s:

Levodopa, together with carbidopa, is the ‘gold standard’ of treatment of motor signs and symptoms. Carbidopa is  a peripheral decarboxylase inhibitor (PDI), which provides for an increased uptake of levodopa in the central nervous system. As shown above, levodopa (denoted as L-DOPA) is converted to dopamine by the dopaminergic neurons. Levodopa is still the most effective drug for managing Parkinson’s motor signs and symptoms. Over time, levodopa use is associated with issues of “wearing-off” (motor fluctuation) and dyskinesia.  For further information about levodopa and dopamine, please see this previously posted topic (click here).

Catechol-O-methyl transferase (COMT) inhibitors prolong the half-life of levodopa by blocking its metabolism. COMT inhibitors are used primarily to help with the problem of the ‘wearing-off’ phenomenon associated with levodopa.

Dopamine agonists are ‘mimics’ of dopamine that pass through the blood brain barrier to interact with target dopamine receptors. Dopamine agonists provide symptomatic benefit and delay the development of dyskinesia compared to levodopa.  Dopamine agonists are not without their own side-effects, which can occur in some patients, and include sudden-onset sleep, hallucinations, edema, and impulse  behavior disorders.  For more information about dopamine agonists,  please see this previously posted (click here).

Finally, monoamine oxidase (MAO)-B is an enzyme that destroys dopamine; thus, MAO-B inhibitors help prevent the destruction of dopamine in the brain. MAO-B inhibitors have some ability to reduce the symptoms of Parkinson’s. The most common severe side effects of MAO-B inhibitors include constipation, nausea, lightheadedness, confusion, and hallucinations.  There may also be contraindications between MAO-B inhibitors with other prescription medications,  vitamins, and certain foods/drinks (e.g., aged cheese and wine). Definitely talk to your doctor and pharmacist about potential drug interactions if you are considering an MAO-B inhibitor in your therapeutic regimen.

“You should just do the right thing.” Dean Smith

What are clinical trials? The simple description is that a clinical trial determines if a new test or treatment works and is safe. The National Institutes of Health (NIH) defines a clinical trial (paraphrased here) as a research study where human subjects are prospectively assigned1 to one or more interventions2 (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.[1The term “prospectively assigned” refers to a predefined process (e.g., randomization) in an approved protocol that stipulates the assignment of research subjects (individually or in clusters) to one or more arms (e.g., intervention, placebo, or other control) of a clinical trial.2An intervention is defined as a manipulation of the subject or subject’s environment for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints.  3Health-related biomedical or behavioral outcome is defined as the prespecified goal(s) or condition(s) that reflect the effect of one or more interventions on human subjects’ biomedical or behavioral status or quality of life.]  For the complete NIH definition, please click here.

As described by ‘’, clinical trials are performed in phases; each phase attempts to answer a separate research question. Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.Phase III:  The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely. Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug’s effect in various populations and any side effects associated with long-term use. A more complete description is included here (click here).

What is important to remember is that clinical trials are experiments with unknown outcomes that must follow a rigorous approach to safely evaluate and possibly validate potential treatments.

“Nothing has ever been accomplished in any walk of life without enthusiasm, without motivation, and without perseverance.” Jim Valvano

NET-PD-LS1 clinical trial went bust on creatine use in treating Parkinson’s: The NET-PD-LS1 clinical trial went from March 2007 until July 2013. NET-PD-LS1 was a multicenter, double blind, placebo-controlled trial of 1741 people with early Parkinson’s. The goal of NET-PD-LS1 was to determine if creatine could slow long-term clinical progression of Parkinson’s (to learn more about this clinical trial go here or go here) . NET-PD-LS1 was one of the largest and longest clinical trials  on Parkinson’s . This clinical trial was stopped after determining there was no benefit to using creatine to treat Parkinson’s.

“It’s what you learn after you know it all that counts.” John Wooden

NET-PD-LS1 clinical trial gets a ‘gold star’ for MAO-B inhibitors in treating Parkinson’s: NET-PD-LS1 was  a thorough and well organized clinical trial.  New results have been published in a secondary analysis of the clinical trial to determine if MAO-B inhibitors for an extended time affected the symptoms of Parkinson’s. Almost half (784) of the patients in NET-PD-LS1 took an MAO-B inhibitor. The MAO-B inhibitors used in NET-PD-LS1 were Rasagiline (Brand name Azilect) and Selegiline (Brand names Eldepryl, Zelapar, or EMSAM).  More than 1600 of the patient’s completed both baseline and one year evaluation/assessment measuring changes in their symptoms (this was done using a combination of five different measurement scales/systems).  Their results were exciting; the patients that were taking an MAO-B inhibitor for a longer time (1 year) had a slower clinical decline (~20% benefit in the magnitude of the decline compared to the patients not taking an MAO-B inhibitor).  These results indicate that MAO-B inhibitors  somehow are able to slow the progression of the symptoms of Parkinson’s.

“Always look at what you have left. Never look at what you have lost.” Robert H. Schuller

Does this prove that MAO-B inhibitors are neuroprotective in Parkinson’s?   The hopeful person inside of me  wants this answer to be yes; however, the scientist that also resides inside of me says no not quite yet.  The goal of neuroprotection is to slow or block or reverse progression of Parkinson’s; and by measuring changes in dopamine-producing neurons.  Early basic science results with MAO-B inhibitors found some neuroprotection in model systems. This new publication reignites the storyline that MAO-B inhibitors are potentially neuroprotective.

“Efforts and courage are not enough without purpose and direction.” John F. Kennedy

A personal reflection about the strategy for treatment of Parkinson’s: MAO-B inhibitors have never been part of my strategy for treating my disorder. I have been using a traditional drug therapy  protocol [Sinemet and Ropinirole] (click here),  supplemented by a  relatively comprehensive CAM approach (click here), bolstered hopefully by a neuroprotective (experimental) agent [Isradipine] (click here), and fortified with as much exercise in my day that my life can handle (click here).  However, there is a constant and dynamic flux/flow of ideas regarding treatment options for Parkinson’s. Thus,  my strategy for treating my disorder needs to be fluid and not fixed in stone. Over the next few weeks, I will be reading more about MAO-B inhibitors, having some serious conversations with my Neurologist and Internist,  with my care partner assessing the risk and benefits of taking an MAO-B inhibitor, and coming up with a consensus team opinion about whether or not I should start taking an MAO-B inhibitor.

Addendum- FDA Approves Xadago for Parkinson’s Disease:
As the Eagles sing in New Kid In Town, “There’s talk on the street; it sounds so familiar / Great expectations, everybody’s watching you”. The first new drug in a decade to treat Parkinson’s is an MAO-B inhibitor named Xadago (Safinamide).  This drug has an interesting past with the FDA before getting approved this week. Is it different? Xadago is for patients using levodopa/carbidopa that are experiencing troublesome “off episodes”, where their symptoms return despite taking their medication. Thus, Xadago is being marketed as an add-on therapy, which is different than existing MAO-B inhibitors because they can be used as stand alone monotherapy. In two separate clinical trials for safety and efficacy of Xadago, compared to patients taking placebo, those taking Xadago showed more “on” time and less “off” time. Interestingly, this is exactly what you’d expect for an MAO-B inhibitor  (sustaining dopamine, see drawing above).  The most common adverse side-effects reported were uncontrolled involuntary movement (side-note: isn’t this what we’re trying to prevent in the first place?), falls, nausea, and insomnia. Clearly, taking Xadago with another MAO-B inhibitor would not be good. Xadago joins a list of other MAO-B inhibitors that are FDA approved for Parkinson’s including Selegiline (Eldepryl, Zelapar, EMSAM) and Rasagiline (Azilect). Whether the efficacy of Xadago is different or improved from existing MAO-B inhibitors remains to be shown; however, having another MAO-B inhibitor may allow Parkinson’s patients the possibility to use the one with the least adverse reactions.  Clearly, close consultation with your Neurologist will be very important before adding any MAO-B inhibitor to your daily arsenal of drugs.  The good news is now you’ve got another option to join the stable of possible MAO-B inhibitors to be used with levodopa/carbidopa.

For the background/rationale behind using “Go the distance” in the title, watch this video clip: Field of Dreams (3/9) Movie CLIP – Go the Distance (1989) HD by Movieclips  (click here to watch Go the Distance).

“Only the mediocre are always at their best. If your standards are low, it is easy to meet those standards every single day, every single year. But if your standard is to be the best, there will be days when you fall short of that goal. It is okay to not win every game. The only problem would be if you allow a loss or a failure to change your standards. Keep your standards intact, keep the bar set high, and continue to try your very best every day to meet those standards. If you do that, you can always be proud of the work that you do.” Mike Krzyzewski

Cover photo image:

Dopamine neurons for the drawing wermodified from



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.

“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.
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. “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) (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: summer-sunset-on-beach-hd.jpg




Déjà Vu and Neuroplasticity in Parkinson’s

“Continuous effort – not strength or intelligence – is the key to unlocking our potential.” Winston S. Churchill

“…remember that what has once been done may be done again.” Alexandre Dumas

Introducing the terms:
éjà vu: “A feeling of having already experienced the present situation.” (

Neuroplasticity: “The brain’s ability to reorganize itself by forming new neural connections throughout life. Neuroplasticity allows the neurons (nerve cells) in the brain to compensate for injury and disease and to adjust their activities in response to new situations or to changes in their environment.” ( )

Do you remember learning how to ride a bike, throw/catch a baseball, and/or hit a golf ball? Yes, yes, yes; when I was a child with my father.
Learning to ride a bicycle
–  training wheels, then two wheels with support from my dad going down the street, and then he let me go on my own; never to forget how to balance and pedal the bicycle.
Learning how to catch and throw a baseball– wrapping up the ball in the mitt to get it conditioned, the  correct throwing motion, watching the thrown ball into the mitt and working on my hand-to-eye coordination.
Learning the basics of the golf swing– the complexity and intricate timing of swinging a golf club with my dad showing me how to do it from grip, set-up, back swing to follow through.
We likely all have childhood memories of activities where our brain and body were trained/taught to do something.

“Neurons that fire together wire together. Mental states become neural traits. Day after day, your mind is building your brain. This is what scientists call experience-dependent neuroplasticity,” Rick Hanson

Déjà vu and physical activity with Parkinson’s: As someone who has loved to exercise almost every day for most of my life, Parkinson’s is a most disagreeable disorder. Why? Let me give you an example of playing golf. I think about playing golf almost every day although I play maybe once a week and try to practice a couple of times per week. It used to be, every time I addressed the golf ball, my body remembered what it’s supposed to do while waiting for the signals from the brain. Now today, approaching the golf ball I remind myself this is a golf shot. As Yogi Berra said “It’s like déjà vu, all over again” and I remember I’ve been here many times before. It’s as if a short circuit exists and I’m realigning this circuitry every time I swing the golf club. For the most part, my brain-body connection still works and I successfully hit the golf ball; but not every time (maybe I just need to practice more?). This might be analogous to a car running very low on transmission fluid (i.e., in my case low on dopamine); the gears are still working but just not working very smoothly.

“Never give up. It’s like breathing—once you quit, your flame dies letting total darkness extinguish every last gasp of hope. You can’t do that. You must continue taking in even the shallowest of breaths, continue putting forth even the smallest of efforts to sustain your dreams. Don’t ever, ever, ever give up.” Richelle E. Goodrich

Neuroplasticity and physical activity: Kleim and Jones (2008) and Petzinger et al. (2013) describe neuroplasticity as a process where the brain encodes experiences and is able to learn new behavior. They define neuroplasticity as the modification of existing neural networks by adding or modifying synapses in response to changes in behavior or environment, especially when done with exercise. Thus, neuroplasticity can help repair and strengthen the circuitry of the brain.  There is substantial evidence in human studies and in rodent-experimental models that have validated numerous exercise-associated effects on “brain health”.  A regular aerobic exercise program likely helps to promote the appropriate conditions for the injured brain to undergo neuroplasticity. 

“Among other things, neuroplasticity means that emotions such as happiness and compassion can be cultivated in much the same way that a person can learn through repetition to play golf and basketball or master a musical instrument, and that such practice changes the activity and physical aspects of specific brain areas.” Andrew Weil

Neuroplasticity and physical activity in Parkinson’s: [Please remember I am not a physician; I’m not making recommendations for you to do something.  Please talk with your neurologist and/or family practitioner before beginning any of these exercise programs.]  Balance, gait-improvement and flexibility are some of the obvious things a person with Parkinson’s needs to address on a frequent basis, in fact, on a daily basis. Clearly this needs to be self-motivated in the interest of possible neuro-rehabilitation. Most experts suggest that the exercise program should be repetitive, intense, and challenging.   Of course, you must enjoy the exercise program.   Ultimately, exercising should hopefully improve motor functions  and also assist  in improving cognitive function.

The exercises that have been most widely studied and proven to be the most beneficial in promoting neuroplasticity are  treadmill training, amplitude training, tai chi, tango dancing, boxing and cycling  (there are many other exercises to consider, don’t be limited by these above). In my opinion, it’s doing the aerobic exercise you enjoy on a daily and sustained basis,  it’s getting range of motion, and its challenging to you mentally.  As a scientist, I’m impressed by the data in rodent Parkinson’s models and the ability of exercise to promote neuroplasticity, to provide neuroprotection, and even offer neurorestoration. In human studies, the results are remarkably strong as well; showing that sustained aerobic exercise induces neuroplasticity in a damaged brain to improve overall brain health.

“Things don’t go wrong and break your heart so you can become bitter and give up. They happen to break you down and build you up so you can be all that you were intended to be.” Charles Jones

Neuroplasticity and physical activity on overall brain health in Parkinson’s. There is substantial scientific evidence that goal-directed aerobic exercise can improve and strengthen motor circuitry. This is due to structural modifications of synapses and overall improved brain health (increased blood flow, enhanced innate immune system and possibly neurogenesis). Overall brain health initiated by exercise-dependent neuroplasticity alters behavior (affecting many areas of the brain, e.g., the basal ganglia,  cortex, thalamus, and cerebellum). Ultimately, the net effect of sustained exercise and neuroplasticity results in improved motor skills, executive function, cognitive function and mood and motivation.  The diagram below illustrates the changes that can occur with exercise-induced neuroplasticity in Parkinson’s.


“Any man could, if he were so inclined, be the sculptor of his own brain.” Santiago Ramón y Cajal

Three comments on déjà vu, neuroplasticity  and physical activity in Parkinson’s:
#1,  Maybe you’re thinking that I’m 62 y.o. and just less coordinated on the golf course with or without Parkinson’s. No doubt this is true but I have my déjà vu feeling, there’s clearly some brain-body disconnect with Parkinson’s (I do need to keep practicing to get more consistent).
#2,  Exercise-induced neuroplasticity will not reverse the effects of Parkinson’s. However, many different studies suggest some restoration of brain circuitry due to exercise-induced neuroplasticity. This implies with time and effort to exercise one could somewhat improve motor learning and behavior performance.
#3, We have much to learn about neuroplasticity and yes even déjà vu. The brain is a powerful organ capable of many different changes when impacted by damage. As we further delineate the mechanism of exercise-induced neuroplasticity, we will better understand Parkinson’s.  Hopefully, from this research (some references are below), there exists the prospect of improved treatment of Parkinson’s. Always remember, a regular aerobic exercise program is good for both your heart and your brain.  Stay positive, be focused, remain hopeful and enjoy your daily exercise.

“Be patient toward all that is unsolved in your heart and try to love the questions themselves, like locked rooms and like books that are now written in a very foreign tongue. Do not now seek the answers, which cannot be given you because you would not be able to live them. And the point is, to live everything. Live the questions now. Perhaps you will then gradually, without noticing it, live along some distant day into the answer.” Rainer Maria Rilke

Cover Photo Credit:


Alberts JL, Linder SM, Penko AL, Lowe MJ, Phillips M. It is not about the bike, it is about the pedaling: forced exercise and Parkinson’s disease. Exerc Sport Sci Rev. 2011;39(4):177–86. [PubMed]

Combs SA, Diehl MD, Staples WH, et al. Boxing Training for Patients With Parkinson Disease: A Case Series. Phys Ther. 2010;91(1):132–42. [PubMed]

Corcos DM, Comella CL, Goetz CG. Tai chi for patients with Parkinson’s disease. N Engl J Med. 2012;366(18):1737–8. [PubMed]

Farley BG, Koshland GF. 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. 2005;167(3):462–7. [PubMed]

Fisher BE, Wu AD, Salem GJ, et al. The effect of exercise training in improving motor performance and corticomotor excitability in people with early Parkinson’s disease. Arch Phys Med Rehabil. 2008;89(7):1221–9. [PMC free article] [PubMed]

Fox CM, Ramig LO, Ciucci MR, Sapir S, McFarland DH, Farley BG. The science and practice of LSVT/LOUD: neural plasticity-principled approach to treating individuals with Parkinson disease and other neurological disorders. Semin Speech Lang. 2006;27(4):283–99. [PubMed]

Gajewski PD, Falkenstein M. Physical activity and neurocognitive functioning in aging – a condensed updated review. European Review of Aging and Physical Activity. 2016;13:1. doi:10.1186/s11556-016-0161-3.

Hackney ME, Earhart GM. Effects of dance on movement control in Parkinson’s disease: a comparison of Argentine tango and American ballroom. J Rehabil Med. 2009;41(6):475–81. [PMC free article] [PubMed]

Heremans E, Nackaerts E, Vervoort G, Broeder S, Swinnen SP, Nieuwboer A. Impaired Retention of Motor Learning of Writing Skills in Patients with Parkinson’s Disease with Freezing of Gait. Allodi S, ed. PLoS ONE. 2016;11(2):e0148933. doi:10.1371/journal.pone.0148933.

Kleim JA, Jones TA. Principles of experience-dependent neural plasticity: implications for rehabilitation after brain damage. J Speech Lang Hear Res. 2008;51(1):S225–39. [PubMed]

Li F, Harmer P, Fitzgerald K, et al. Tai chi and postural stability in patients with Parkinson’s disease. N Engl J Med. 2012;366(6):511–9. [PMC free article] [PubMed]

Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW. Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease. Lancet Neurol. 2013; 12(7):716–726. doi: 10.1016/S1474-4422(13)70123-6 [PMC free article] [PubMed]

Voss MW, Vivar C, Kramer AF, van Praag H. Bridging animal and human models of exercise-induced brain plasticity. Trends in cognitive sciences. 2013;17(10):525-544. doi:10.1016/j.tics.2013.08.001.


Importance of Model Systems in Parkinson’s Research

“Science is organized knowledge. Wisdom is organized life.” Will Duran

“The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’ but ‘That’s funny…’” Isaac Asimov

Introduction:  The goal of this post is to highlight several experimental model systems that have effectively been used in Parkinson’s research.  We  have gained tremendous knowledge about all aspects of Parkinson’s from the use of model systems (Please note there are many publications that could have been included here by many different outstanding scientists; this is just a sampling of the strong science in the field of Parkinson’s disease).

The alpha-synuclein story in Parkinson’s: Alpha-synuclein is  a protein found in the brain that form aggregates (clumps of protein) called Lewy bodies.   Lewy bodies accumulate inside the substantia nigra region of the brain and they are toxic to the neurons and they no longer synthesize dopamine.   Part of the toxicity of alpha-synuclein-forming Lewy bodies is linked to mitochondria inhibition,  the little energy factories found in  our cells. This is just a sampling of alpha-synuclein in Parkinson’s (here is a PubMed search: ).

“Science is the process that takes us from confusion to understanding…” Brian Greene

The need for experimental model systems:  Scientists develop and use various experimental tools to answer their research questions. The ‘strength’ of the observation is usually dependent on the ‘quality’ of the experimental model system. Described here are four of many different experimental model systems: yeast; Caenorhabditis elegans (C. elegans); human, rat or mouse neuronal cells; and the mouse (or rat). Ultimately, scientists and physicians ‘translate’ this information for use in human clinical trials, which defines the phrase “bench-to-bedside”.


“I never guess. It is a capital mistake to theorize before one has data. Insensibly one begins to twist facts to suit theories, instead of theories to suit facts.” Sir Arthur Conan Doyle, Author of Sherlock Holmes stories

Advancing our understanding of Parkinson’s using experimental model systems: You must remember a couple of things about science and research in general. Asking and answering one question usually leads to another question that needs to be answered. Typically, the next questions are more complex as the story unfolds. It is kind of like peeling an onion, you start taking off the top layer and you keep going; the more questions you answer the more layers you have to peel. Let’s go peel some onions.

Rising yeast in biology:  In our everyday lives,  baker’s yeast is used to make bread and alcoholic beverages like beer.  Yeast are single cell organisms, but like human cells they are eukaryotic (defined as “…cells that contain a distinct membrane-bound nucleus and by the occurrence of DNA transcription inside the nucleus and protein synthesis in the cytoplasm….” ). Yeast are easy to culture and they share many similarities to human cells;  furthermore, genetic manipulation is relatively easy to do in yeast and offers a powerful tool for biomedical science. [Also see

Use of yeast in Parkinson’s research Tardiff and others performed a really clever experiment, they expressed alpha-synuclein in yeast.  They found that yeast, just like human neuronal cells, got sick in the presence of excess amounts of alpha-synuclein.  They used the yeast expressing alpha-synuclein  and asked the following questions. Could a compound neutralize or reverse the alpha-synuclein-induced toxicity in yeast? Would this compound be able to restore normal function to the yeast?  They tested  ~190,000 compounds to see whether any of those would reverse the toxic effects and allow the yeast to rapidly grow again.  One lead compound evolved from this study, N-aryl benzimidazole (NAB).  NAB corrected the problem in yeast expressing alpha-synuclein. Using elegant genetics, they found that NAB activates a “trafficking” protein named Rsp5. The alpha-synuclein-induced toxicity  was inhibiting the function of Rsp5, which means that NAB reverses this effect. This sets the scene for new pathways to be explored for how Parkinson’s evolves, and presents a new strategy for exploring drugs to treat this disorder.
Tardiff DF, Jui NT, Khurana V, et al. Yeast reveal a “druggable” Rsp5/Nedd4 Network that Ameliorates α–Synuclein Toxicity in Neurons. Science (New York, NY). 2013;342(6161):979-983. doi:10.1126/science.1245321.

“Science is a way of thinking much more than it is a body of knowledge.” Carl Sagan

“Worm people” advancing science using C. elegans: C. elegans are non-parasitic soil nematodes that are free-living (…worms of the phylum Nematoda, having unsegmented cylindrical bodies often narrowing at each end, and including free-living species that are abundant in soil and water, and species that are parasites of plants and animals…” ). C. elegans is a model organism due to its ability to be easily grown and manipulated genetically, which scientists use to advance complex biological principles.  [Also see

Use of worms in Parkinson’s research Advanced age is the greatest known risk factor for development of Parkinson’s.  Why this happens is not fully understood. Cooper and others proposed the following hypothesis: “…there are specific changes that take place during the aging process that make cells susceptible to disease-causing mutations that are well-tolerated at younger ages.” To begin to ‘test’ this hypothesis, they used genetics and C. elegans as a model system.  Worms containing mutations in the daf-2 gene live twice as long as control worms.  The researchers crossed  C. elegans models of Parkinson’s with daf-2 mutants.  Compared to the appropriate control worms, the Parkinson’s/daf-2 mutant worms had longer lifespan, protection of dopamine neurons, resistance to inflammatory stress, and decreased Lewy-body formation. This C. elegans genetics-aging study implies that slowing down the aging process is neuroprotective in Parkinson’s.
Jason F Cooper, Dylan J Dues, Katie K Spielbauer, Emily Machiela, Megan M Senchuk, and Jeremy M Van Raamsdonk. Delaying aging is neuroprotective in Parkinson’s disease: a genetic analysis in C. elegans models. npj Parkinson’s Disease (2015) 1, 15022; doi:10.1038/npjparkd.2015.22; published online 19 November 2015

“What we find changes who we become.” Peter Morville

Cells provide a cultivating environment to model tissues/organs:  Over the past several decades, many different types of cells have been grown in sterile plastic dishes; ranging from “primary” cell extracts obtained from different organs to “immortalized” cell types from various tumor types (i.e., cancer).  Cells grown in vitro (defined as “performed or taking place in a test tube, culture dish, or elsewhere outside a living organism” do not fully recapitulate the organ of origin; nonetheless, cell culture is a powerful model system to study both normal biological and abnormal pathological processes. [Also see

Use of neuronal cells in Parkinson’s research Proteins have unique three-dimensional shapes, which encode their biological activity.  Sometimes, proteins go bad and do things that are pathological like alpha-synuclein forming aggregates. Moree and others are testing a hypothesis that small molecules can be discovered that reverse such detrimental protein aggregation. They developed a novel screening technique to identify compounds that modulate protein conformation (which is way beyond the scope of this blog posting). They discovered a compound named BIOD303 as a novel conformational modulator of alpha-synuclein.Interestingly, these modulators reduced alpha-synuclein aggregation in an experimental neuronal cell model. This sort of study could (possibly one day) lead to a novel process for treating Parkinson’s by reversing alpha-synuclein aggregates.
Moree B, Yin G, Lázaro DF, et al. Small Molecules Detected by Second-Harmonic Generation Modulate the Conformation of Monomeric α-Synuclein and Reduce Its Aggregation in Cells. The Journal of Biological Chemistry. 2015;290(46):27582-27593. doi:10.1074/jbc.M114.636027.

“Science does not know its debt to imagination.” Ralph Waldo Emerson

The mouse (rat) provides a most important model system:  Our understanding of many human diseases (think cardiovascular, cancer, and yes, Parkinson’s) has been advanced using mice and rats as model systems. One reason why mice are used is the similarity of mouse and human genetics. Scientists have done amazing feats using mice including “gene knockout” where specific genes have been deleted or inactivated.  Another type of mouse genetically-derived is the “transgenic mice”, which usually express genes thought to promote human diseases.  Ultimately, a mouse (or rat) with a specific disease becomes a model or ‘stand-in’ for that same human disease or condition.  [Also see

Use of rats in Parkinson’s researchVolakakis and others studied how alpha-synuclein promotes changes in dopamine-producing neurons. They found that alpha-synuclein alters gene expression and that a transcription factor (a protein that binds to specific DNA sequences that modulates the genetic information being transcribed from DNA to messenger RNA) known as Nurr1 helps resist these effects. They found that nuclear substances that bind to Nurr1’s partner retinoid X receptor (RXR) also had a neuroprotective role. Their results clearly highlight Nurr1’s neuroprotective role against alpha-synuclein-induced changes in dopamine-producing neurons. Furthermore, their results imply that RXR ligands have therapeutic potential in Parkinson’s.
Volakakis N, Tiklova K, Decressac M, Papathanou M, Mattsson B, Gillberg L, Nobre A, Björklund A, Perlmann T. Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression. J Neurosci. 2015 Oct 21;35(42):14370-85. doi: 10.1523/JNEUROSCI.1155-15.2015. PMID:26490873

“Barry L. Jacobs and colleagues from the neuroscience program at Princeton University showed that when mice ran every day on an exercise wheel, they developed more brain cells and they learned faster than sedentary controls. I believe in mice.”  Bernd Heinrich

From bench-to-bedside: The four papers described here represent the tip-of-the-iceberg in Parkinson’s research. As with any basic science study, the next step, the next few years are key to developing/advancing/evaluating these questions and getting answers. I am optimistic that new compounds, new treatment strategies, and further understanding of Parkinson’s are coming in the near future. It just will take time, so we must remain patient while all of their research endeavors progress.

“From the standpoint of daily life, however, there is one thing we do know: that we are here for the sake of each other – above all for those upon whose smile and well-being our own happiness depends, and also for the countless unknown souls with whose fate we are connected by a bond of sympathy. Many times a day I realize how much my own outer and inner life is built upon the labors of my fellow men, both living and dead, and how earnestly I must exert myself in order to give in return as much as I have received.” Albert Einstein

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