Category Archives: Parkinson’s Disease

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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Driving Under the Influence of Parkinson’s

“Have you ever noticed that anybody driving slower than you is an idiot, and anyone going faster than you is a maniac?” George Carlin

“If all the cars in the United States were placed end to end, it would probably be Labor Day Weekend.” Doug Larson

The Dilemma: At some age in our life, maybe, just maybe, we could lose the privilege of driving our car/truck.  If you are living with Parkinson’s, depending on the individual, losing the legal right to drive your motor vehicle might/could happen at an even earlier age.  A discussion of driving under the influence of Parkinson’s is presented here.

“I love driving cars, looking at them, cleaning and washing and shining them. I clean ’em inside and outside. I’m very touchy about cars. I don’t want anybody leaning on them or closing the door too hard, know what I mean?” Scott Baio

The Michon model of normal driving behavior:  In 1985, Michon proposed that drivers need to conduct problem-solving while driving; he divided it  into three levels of skill and control. The model includes strategic (planning), tactical (maneuvering), and operational (control) levels.   When you think about it driving really is a complicated task.   The strategic level is basically the general route and planning needed to successfully navigate the motor vehicle.  The tactical and control levels involve the individual driving circumstances and how one responds and our responsiveness to the action of driving.   And of course, it’s quite obvious, that unsafe driving is operating a motor vehicle in an unsafe manner regardless of your health status. Driving safely is important for the individual as well as for the people around you; thus, it is a serious task to evaluate someone’s competency to drive a motor vehicle. Shown below is a schematic drawing of the Michon model of normal driving behavior.

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“The one thing that unites all human beings, regardless of age, gender, religion, economic status, or ethnic background, is that, deep down inside, we all believe that we are above-average drivers.” Dave Barry

Decision-making while driving:   Below are some traffic signs that we might encounter in our usual driving pattern depending on where we live. When you think about decision-making you’re in your lane you’re driving down the road and you see signs like this, then what?  You can see how it takes all three levels of driving competency to navigate successfully while driving a motor vehicle in a complex maneuver.  Now add the complications of someone with Parkinson’s, you may need to re-think the entire situation. What this says is that when you’re driving a motor vehicle you’re trying to integrate many levels of sensory, motor and cortical function to the process. In Parkinson’s, we may have some sort of motor skill/task impairment, potentially mixed with a minor cognitive disorder, and further clouded by traditional drug therapy. Who makes the decision for the patient with Parkinson’s about being able to continue to drive?  Not an easy answer.

“Some beautiful paths can’t be discovered without getting lost.” Erol Ozan

 Possible problems that could occur while driving with Parkinson’s: The control or operational level of driving a car can be influenced by motor defects experienced by many with Parkinson’s, including rigidity, tremor, bradykinesia and dyskinesia. Futhermore, non-motor deficits could impair both route planning, strategic and tactical levels, and these would include cognitive decline, neuropsychiatric symptoms and/or visual impairment. And on top of that in the elderly population, many people with Parkinson’s have additional co-morbidity that could also contribute to diminish our ability to drive a motor vehicle. Thinking about just one aspect, slowness in cognitive function, the inability to make a decision quickly could lead to poor performance time and might affect driving in someone with Parkinson’s. Alternatively, you may have none of these problems and will be driving for many more years. But as we all start to exhibit signs and symptoms of motor and non-motor deficits, this will eventually become an important issue for each of us to deal with at some point in time.

“Always focus on the front windshield and not the review mirror.” Colin Powell

 What are some criteria for determining our fitness to drive a motor vehicle when you have Parkinson’s? In a very nice review, Jitkritsadakul and Bhidayasiri suggest there are five different red flags that should tell our neurologist that we may have an impairment that should limit our driving of motor vehicles. First, these include our clinical history, which would be a history of accidents, sleeping attacks while driving and combined with the daily dose amount of levodopa. Next would be a questionnaire to determine our level of daily sleepiness. Third, a motor assessment skills test. Fourth, a cognitive assessment. And fifth would be a visual assessment.  Look above at the Michon driving schematic and think about the three levels of skill required for driving and substitute someone with Parkinson’s and how that could diminish one or more of the skill sets over time.  What this says to me is that through a combination of family and friends and carepartner,  along with the advice of our neurologist, one should be able to make a critical assessment of whether or not we should continue to drive.

“Driving your car through deep pools of flood water is a great way of making your car unreliable. Smart people turn around and avoid it.” Steven Magee

A love of motor vehicles (a personal expression):  I grew up loving automobiles; and living on Air Force Bases, I saw many different types of sports cars  (e.g., Corvette, Jaguar, Triumph, Porsche, Shelby Mustang, Ferrari- you just had to believe that Air Force pilots live for speed in the air and their cars showed it on the ground). I can remember in 1964 (I was 11 years old) going to the Ford dealership with my dad to see the very first Ford Mustang cars; thinking how beautiful they were and remembering my dad’s comment that was a lot of car for $2,400.   I still have vivid memories of riding with my dad (yes, he was a former pilot) in his ~1962 white Porsche. I can still remember in 1971 getting my first car, a 1968 Chevrolet Camaro (red interior and red exterior) with standard transmission (three on the floor) and powered by a 327 cubic inch V-8 engine. [Please note, the pictures below are representative images because I could not find any actual old photos of these cars]

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Over the decades, I can recall the weekly car-washing sessions, typically on Saturday mornings. With the exception of one car in the early 1980’s, I have loved and truly enjoyed the automobiles I’ve driven.  Like many people I’ve named all my cars; my two current automobiles are named Raven and Portia. I still enjoy driving a standard shift car using the clutch that requires both cognitive function and motor skills to navigate the automobile. I have always thought “It’s going to be a cold day in hell before they take my car away”; however, it’s a reality in the future I now face with Parkinson’s. In fact one of the very first people I ever told about my Parkinson’s several years ago, the very first question she asked me was “Are you still able to drive?”  In summary, driving under the influence of Parkinson’s is something we all will need to consider with time; I wish you well with your driving experiences.

“Driving a car provides a person with a rush of dopamine in the brain, which hormonal induced salience spurs modalities of creative and critical thinking regarding philosophical concepts such as truth, logical necessity, possibility, impossibility, chance, and contingency.” Kilroy J. Oldster

https://www.ncbi.nlm.nih.gov/pubmed/27729986

1.    Jitkritsadakul O, Bhidayasiri R. Physicians’ role in the determination of fitness to drive in patients with Parkinson’s disease: systematic review of the assessment tools and a call for national guidelines. Journal of Clinical Movement Disorders. 2016;3(1):14. doi: 10.1186/s40734-016-0043-x.

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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 (https://en.oxforddictionaries.com/definition/empathy). 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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Life-Journey with Parkinson’s Blog (2016-2017): Recap of Quotes, Service, and Research

“Give your life a destination.” Debasish Mridha

“We’re all a beautiful, wonderful work in progress….Embrace the process!” Nanette Mathews

Précis: This post is a review of my public journey and life-steps with Parkinson’s in the 2nd year of the blog: i) rationale for the blog; ii) quotes/highlights from selected posts between March 2016-March 2017; iii) overview of service activities/events; iv) research and the 4th World Parkinson Congress; v) some of the people that make a difference in my life, and vi) six favorite cover photos from the past year.

Update on I’m Still Here: Journey and Life with Parkinson’s

A thought from Day 01: On March 9, 2015, I began my journey and Parkinson’s-life-story with this blog.  The first blog post ended with the following comment: “I am trying to live life well and authentically, and not be defined by my PD. With the help of family, friends, colleagues, and personal physicians, my goals are to stay positive and strive to keep focused on what matters the most…I am still here!”

Foundational themes of the blog:  The overall goal of the blog is divided between these topics: (a) to describe living with Parkinson’s (“Life Lessons”); (b) to present emerging medical strategies for dealing with Parkinson’s (“Medical Education”); (c) to provide a support mechanism for anyone with Parkinson’s or another neurodegenerative disorder (“Strategy for Living”); and (d) to give an overview of the scientific aspects of Parkinson’s (“Translating Science”).  I really appreciate your continual support, feedback, critiques, and suggestions for future topics (here’s an example): “I enjoy reading your informative blog posts. I believe that addressing the many frustrations of living with Parkinson’s as you are doing with such “matter of factness” and then with a plan of action, must be inspiring to others dealing with the same.  All the while working so hard to maintain your positive outlook…the mental exercise! The other side of the overall challenge in this competition with Parkinson’s Disease to live your present life fully.” If there are some specific topics/life aspects of Parkinson’s you’d like for me to research and present here, please send me the topic(s).  If there is some format change in presentation you’d like to see to improve the readability of future posts, please send me a suggestion.

Quotes and highlights from selected posts from March 2016-March 2017:

  1. “As a long-time educator, I feel that my daily lesson plans are partly derived from my life-experiences and that my syllabus is the sum of my life’s journey.”  From Parkinson’s and the Positivity of Michael J. Fox (click here to read post).
  2. “A regular aerobic exercise program likely helps to promote the appropriate conditions for the injured brain to undergo neuroplasticity.”  From Déjà Vu and Neuroplasticity in Parkinson’s (click here to read post).
  3. We are identified by our characteristic symptoms of our unwanted companion named Parkinson’s. We are all in this together, united by our disorder; held together by those who love and care for us.” From Update on I’m Still Here: Life with Parkinson’s (click here to read post).
  4. While we wait for the potion that slows progression, we exercise and remain hopeful. While we live with a neurodegenerative disorder, we strive to remove the label and we stay positive.” From Parkinson’s Treatment With Dopamine Agonist, Complementary and Alternative Medicine (CAM), and Exercise(click here to read post).
  5. Living with Parkinson’s requires you to adapt to its subtle but progressive changes over a long period of time; you need to remain hopeful for many different things.” From Chapter 1: A Parkinson’s Reading Companion on Hope (click here to read post).
  6. “This disorder robs you physically of mobility and flexibility, so maintaining physical strength is really important. This disorder robs you emotionally and this deficit is bigger than the physical defects; thus, to thrive with Parkinson’s demands several character strengths.” From Chapter 3: A Parkinson’s Reading Companion on Strength (click here to read post).
  7. “Life with Parkinson’s is best lived in the current moment without dwelling on the past and dreading the future.”  From Chapter 8: A Parkinson’s Reading Companion on Mindfulness (click here to read post).
  8. “The journey with Parkinson’s requires effort, teamwork, awareness, and a heart-fueled positive attitude to keep going.”  From Chapter 9: A Parkinson’s Reading Companion on Journey (click here to read post).
  9. “Consider your disorder, you must be able to embrace this unexpected turn in your life and manage the best you can. Personalize your disorder and understand its nuances on you; then you will be able to successfully navigate life in its daily presence.” From 9 Life Lessons from 2016 Commencement Speeches (click here to read post).
  10. “I truly believe that the effort most people are using to handle their disorder puts them in a healthier and better lifestyle to manage their symptoms. An emerging predominate picture of Parkinson’s today is a person striving to live strongly.” From The Evolving Portrait of Parkinson’s (click here to read post).
  11. “Believe in Life in the Presence of Parkinson’s”: Every thought expressed here matters to me (click here to read post).
  12. “Your home may change many times over the coming years. Let your heart tell you where your home is.” From 2016 Whitehead Lecture: Advice, Life Stories and the Journey with Parkinson’s (click here to read post).
  13.  “Here’s a simple mindfulness experience/moment: simply be aware of the steam leaving your morning cup of coffee/tea, clear your immediate thoughts, then sip, focus and savor this moment.”  From 7 Healthy Habits For Your Brain (click here to read post).
  14. “You’ve played 17 holes of golf, and you approach the 18th hole to finish the round. This is a long par three with a lake between you on the tee box and the putting surface.  Your three golf buddies have already safely hit their balls over the lake;  you  launch the ball over the water and safely onto the green (this is a big deal).  Without Parkinson’s, your facial expression and your exuberance are so obvious.  With Parkinson’s, your joy and exuberance are still over-flowing inwardly yet it is displayed in a more muted manner.”  From The Mask of Parkinson’s (click here to read post).
  15. “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.”  From 2016: The Year in Parkinson’s (click here to read post).
  16. “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.”  From 9 Things to Know About Exercise-induced Neuroplasticity in Human Parkinson’s (click here to read post).

Service and research:
Service- I was most fortunate to be able to participate in 2 ways for the 4th World Parkinson Congress (WPC), first as a member of the Communications Committee, World Parkinson Coalition; second, as the Co-Editor, Daily Parkinson eNewspaper for the 4th WPC.  And it gave me an opportunity to work with the very talented Eli Pollard (Executive Director WPC).  A truly amazing Editorial Board was assembled of PD advocates, researchers, experts, PwP, and just a superb group of people devoted to Parkinson’s (click here to read the Editorial Board Biographical Sketches).   This was a meaningful experience to have worked with the Editorial Board, a real honor.

Being part of the Planning Committee, Moving Day NC Triangle, headed up by Jessica Shurer, was such fun.  This was my first year on the committee; however, it was my second year to organize a team for Moving Day.

PWR!Moves® Instructor Workshop Certificate. Spent a weekend in Greenville, SC to participate and get certified in PWR!Moves (PWR = Parkinson Wellness Recovery).  To sum it up is easy, truly an amazing event.  I was fortunate to have an experienced-talented instructor and a group of personal trainers committed to working with PwP (click here to read the blog post describing the PWR! experience). Although I was happy to contribute as the person-with-Parkinson’s and go through the exercise routines for everyone, it was even more fun getting trained and certified in PWR!Moves.

Research-  One of the new directions in my life is a shift in the focus of my research away from hematology and to Parkinson’s.  I keep asking myself, why? and keep answering why not!  The process is just like everything else related to research and grant applications; you read, plan, write, submit, and wait.  However, I am pleased to say that CJ’s fellowship entitled “Localization of Proteases and their Inhibitors in Parkinson’s Disease” was funded by UNC-CH.  It’s a start…we begin gathering data next month.  And I am so proud of CJ for seeking (and obtaining) funding to get us started in the science of Parkinson’s.

“Life is like a roller-coaster with thrills, chills, and a sigh of relief.” Susan Bennett

The people that make a difference in my life: Collectively, everyone here gives me strength each and every day of my journey with this disorder.

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Above- Barbara, the best care-partner/best friend/best everything; I can’t imagine being here and doing all of this without your never-ending love and support.

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Top and bottom right panels above- lab/research group [especially important are CJ (currently working in the lab) and Mac (a long-time collaborator) and Chantelle, Savannah, and Jasmine (no longer working in the lab but still are great friends and vital to our success)]; middle panel- nothing more valuable than family, with my sisters (Tina and Kitty), and bottom left panel- my all-important golf buddies [Walter, Kim, Nigel (not pictured) and John].

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Panels above- undergraduate classes from SP ’16, FA’ 16 and SP ’17 inspire me every day to keep teaching and fuel my inner-core to keep going another year.

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Above panels- medical students (all 180 students/class) enrich my life and challenge me to keep working hard and stay happy.

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Besides attending a Parkinson’s Congress, getting certified in PWR!, publishing a book, and walking for Parkinson’s; it was all made easier by my PWR! Physical Therapist and gifted teacher Jennifer (top right panel), expert medical guidance from my Neurologist Dr. Roque (middle panel), Parkinson’s-education-awareness from the best movement disorder center social-worker Jessica (bottom middle panel), perpetual energy and role model of a PwP-advocate Lisa (bottom right panel), and Johanna and Katie (not pictured above) who make my day-job such a joyful experience.  And I apologize to many others who are not pictured here because you do really matter to me.

6 favorite cover photos from the past year (links to photos at the end):

2016-17a_fav.covers

Thank you! Thank you for your support during the second year of my journey with this blog. As always, live decisively, be positive, stay focused, remain persistent and stay you.

“I want to be in the arena. I want to be brave with my life. And when we make the choice to dare greatly, we sign up to get our asses kicked. We can choose courage or we can choose comfort, but we can’t have both. Not at the same time. Vulnerability is not winning or losing; it’s having the courage to show up and be seen when we have no control over the outcome. Vulnerability is not weakness; it’s our greatest measure of courage.”  Brené Brown, Rising Strong

Noted added in proof: For a day or so, a preliminary version of this post appeared in 200 Years Ago James Parkinson published “An Essay On The Shaking Palsy” (click here to view).  Together, this combined post was substantially longer than my usual blog post.  Therefore, I separated them and decided to present this year-end-review in an expanded format.

Cover photo credit: farm4.staticflickr.com/3953/15575910318_ec35ebb523_b.jpg

Photo credits for the 6 favorite cover photos for 2016-2017: top left http://epod.usra.edu/.a/6a0105371bb32c970b015438c5312a970c-pi;  top right: : http://vb3lk7eb4t.search.serialssolutions.com/?V=1.0&L=VB3LK7EB4T&S=JCs&C=TC0001578421&T=marc ; middle left wallpaper-crocus-flower-buds-violet-primrose-snow-spring-flowers.jpg; middle right : http://az616578.vo.msecnd.net/files/2016/03/19/635940149667803087959444186_6359344127228967891155060939_nature-grass-flowers-spring-2780.jpg ; bottom left : http://www.beaconhouseinnb-b.com/wp-content/uploads/dawn-at-spring-lake-beach-bill-mckim.jpg ; bottom right : http://www.rarewallpapers.com/beaches/lifeguard-station-10678

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Parkinson’s Awareness Month: Veterans Health Administration PD Video Series

“My motto was always to keep swinging. Whether I was in a slump or feeling badly or having trouble off the field, the only thing to do was keep swinging.” Hank Aaron

“Nothing worth having comes easy.” Theodore Roosevelt

Introduction: Several years ago, the Veterans Health Administration produced videos to educate/inform our veterans about Parkinson’s disease.   For more information, read about the VA Core Values and Mission Statement (click here); it is an admirable sentiment.

As we are living longer, so too are our veterans. Some service-related-experiences may have predisposed some of them to develop Parkinson’s.  All of these videos are available on YouTube.  However, since this is Parkinson’s awareness month, putting them all together might benefit others to better understand Parkinson’s.   I definitely learned something from watching these videos, they were all outstanding.

Each individual video features a veteran (frequently their care-partner too) who agreed to be videotaped (having done this type of interview myself, it is not an easy experience); I admire their courage to participate and to help educate all of us. Furthermore, the VA clinical and support staff were passionate and compassionate about their roles in dealing with our veterans with Parkinson’s.

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

Veterans Health Administration – My Parkinson’s Story:
My Parkinson’s Story:
Early Parkinson’s Disease [click here for video]

My Parkinson’s Story: Thinking and Memory Problems with Parkinson Disease [click here for video]

My Parkinson’s Story: Medications [click here for video] 

My Parkinson’s Story: Dyskinesias [click here for video] 

My Parkinson’s Story: Atypical [click here for video] 

My Parkinson’s Story: Driving [click here for video]

My Parkinson’s Story: Sleep Problems and Parkinson’s Disease [click here for video] 

My Parkinson’s Story: Genetics [click here for video] 

My Parkinson’s Story: Exercise [click here for video] 

My Parkinson’s Story: Environmental Exposure [click here for video]

My Parkinson’s Story: The Impact of Depression in Parkinson’s Disease [click here for video] 

My Parkinson’s Story: Impact of Falls and Parkinson’s Disease [click here for video]

My Parkinson’s Story: The Caregiver [click here for video] 

My Parkinson’s Story: Deep Brain Stimulation and Parkinson Disease [click here for video]

My Parkinson’s Story: Hospitalization [click here for video] 

My Parkinson’s Story: Speech and Swallowing [click here for video] 

My Parkinson’s Story: Advanced Parkinsons [click here for video]

“Not I, nor anyone else can travel that road for you. You must travel it by yourself. It is not far. It is within reach. Perhaps you have been on it since you were born, and did not know. Perhaps it is everywhere – on water and land.” Walt Whitman

“We can’t equate spending on veterans with spending on defense. Our strength is not just in the size of our defense budget, but in the size of our hearts, in the size of our gratitude for their sacrifice. And that’s not just measured in words or gestures.” Jennifer Granholm

Cover Photo Credit: http://wallpapersafari.com/w/Fy0h6Q/

Milestones in Parkinson’s Disease Research and Discovery

“The real voyage of discovery consists not in seeking new landscapes, but in having new eyes.” Marcel Proust

“The process of scientific discovery is, in effect, a continual flight from wonder.” Albert Einstein

Preface:  Happy birthday to James Parkinson (neurologist, geologist, scientist, activist),  born April 11, 1755 and died December 21, 1824.  World Parkinson’s Day April 11, 2017.

Introduction to the historical timeline on Parkinson’s disease: This historical description of Parkinson’s is a joint venture/adventure between Frank and Simon . The idea for this project started as a conversation during a recent North Carolina beach weekend for Frank and Barbara: “Wouldn’t it be cool to publish a Parkinson’s historical timeline for Parkinson’s awareness month?” However, to complete this project I needed a Parkinson’s expert. As a follower of his outstanding blog ‘Science of Parkinson’s’, I approached Simon about helping out on this timeline project; and to my delight he said yes. Therefore, we are happy to present the milestones in Parkinson’s disease research and discovery. We do apologize to the clinicians, scientists, health-care specialists, and their projects that were not cited here but we limited the timeline to ~50 notations.

The entire historical timeline can be downloaded (click here for the PowerPoint file) and we encourage you to view it in ‘presentation’ mode. Each individual page of the timeline is presented below along with a brief explanation for each of the highlighted events. And Simon and I will be sharing the historical timeline in our own individual blogs.

“I want to see books taken out of historical time and placed into a different timeline, such as evolutionary or geological time, as a means of putting the human experience in context.” Douglas Coupland

1817-1919, Milestones in Parkinson’s Disease Research and Discovery (Part 1a: Historical):
Slide1

First description of Parkinson’s disease:
In 1811, Mr James Parkinson of no. 1 Hoxton Square (London) published a 66 page booklet called an ‘An Essay on the Shaking Palsy’. At the date of printing, it sold for 3 shillings (approx. £9 or US$12). The booklet was the first complete description of a condition that James called ‘Paralysis agitans’ or shaking palsy. In his booklet, he discusses the history of tremor and distinguishes this new condition from other diseases. He then describes three of his own patients and three people who he saw in the street.

The naming of Parkinson’s disease:
Widely considered the ‘Father of modern neurology’, the importance of Jean-Martin Charcot’s contribution to modern medicine is rarely in doubt. From Sigmund Freud to William James (one of the founding fathers of Psychology), Charcot taught many of the great names in the early field of neurology. Between 1868 and 1881, Charcot focused much of his attention on the ‘paralysis agitans’. Charcot rejected the label ‘Paralysis agitans’, however, suggesting that it was misleading in that patients were not markedly weak and do not necessarily have tremor. Rather than Paralysis Agitans, Charcot suggested that Maladie de Parkinson (or Parkinson’s disease) would be a more appropriate name, bestowing credit to the man who first described the condition. And thus 70 years after passing away, James Parkinson was immortalized with the disease named after him.

The further clinical characterization of Parkinson’s disease:
British neurologist Sir William Gowers published a two-volume text called the Manual of Diseases of the Nervous System (1886, 1888). In this book he described his personal experience with 80 people with Parkinson’s disease in the 1880s. He also identified the subtle male predominance of the disorder and provided illustrations of the characteristic posture. In his treatment of Parkinson’s tremor, Gower used hyoscyamine, hemlock, and hemp (cannabis) as effective agents for temporary tremor abatement.

The discovery of the chemical dopamine:
In the Parkinsonian brain there is a severe reduction in the chemical dopamine. This chemical was first synthesized in 1910 by George Barger and James Ewens at the Wellcome labs in London, England.

The discovery of Lewy bodies:
One of the cardinal features of Parkinson’s disease in the brain is the presence of Lewy bodies – circular clusters of protein. In 1912, German neurologist Friedrich Lewy, just two years out of medical school and still in his first year as Director of the Neuropsychiatric Laboratory at the University of Breslau (now Wroclaw, Poland) Medical School discovered these ‘spherical inclusions’ in the brains of a people who had died with Parkinson’s disease.

The importance of the substantia nigra in Parkinson’s disease:
The first brain structure to be associated with Parkinson’s disease was the substantia nigra. This region lies in an area called the midbrain and contains the majority of the dopamine neurons in the human brain. It was in 1919 that a Russian graduate student working in Paris, named Konstantin Tretiakofirst demonstrated that the substantia nigra was associated with Parkinson’s disease. Tretiakoff also noticed circular clusters in the brains he examined and named them ‘corps de Lewy’ (or Lewy bodies) after the German neurologist Friedrich Lewy who first discovered them.

“Everyone wants answers and wants to know what the timeline is. Unfortunately, it’s a complex situation, and we don’t have the final answers yet.” Dennis Miller

1953-1968, Milestones in Parkinson’s Disease Research and Discovery (Part 1b: Historical):

Slide2

The first complete pathologic analysis of the Parkinsonian brain:
The most complete pathologic analysis of Parkinson’s disease with a description of the main sites of damage was performed in 1953 by Joseph Godwin Greenfield and Frances Bosanquet.

The discovery of a functional role for dopamine in the brain:
Until the late 1950s, the chemical dopamine was widely considered an intermediate in the production of another chemical called norepinephrine. That is to say, it had no function and was simply an ingredient in the recipe for norepinephrine. Then in 1958, Swedish scientist Arvid Carlsson discovered that dopamine acts as a neurotransmitter – a discovery that won Carlsson the 2000 Nobel prize for Physiology or Medicine.

The founding of the Parkinson’s Disease Foundation:
In 1957, a nonprofit organization called the Parkinson’s Disease Foundation was founded by William Black. It was committed to finding a cure for Parkinson’s Disease. Since its founding in 1957, PDF has funded more than $115 million worth of scientific research in Parkinson’s disease. The National Parkinson Foundation (NPF), was also founded in 1957 by Jeanne C. Levey. NPF is a national organization whose mission is to make life better for people with Parkinson’s through expert care and research. The foundation has funded more than $208 million in care, research and support services.

The discovery of the loss of dopamine in the brain of people with Parkinson’s disease:  In 1960, Herbert Ehringer and Oleh Hornykiewicz demonstrated that the chemical dopamine was severely reduced in brains of people who had died with Parkinson’s disease.

The first clinical trials of Levodopa:
Knowing that dopamine can not enter the brain and armed with the knowledge that the chemical L-dopa was the natural ingredient in the preoduction of dopamine, Oleh Hornykiewicz & Walther Birkmayer began injecting people with Parkinson’s disease with L-dopa in 1961. The short term response to the drug was dramatic: “Bed-ridden patients who were unable to sit up, patients who could not stand up when seated, and patients who when standing could not start walking performed all these activities with ease after L-dopa. They walked around with normal associated movements and they could even run and jump.” (Birkmayer and Hornykiewicz 1961).

The first internationally-used rating system for Parkinson’s disease:
In 1967, Melvin Yahr and Margaret Hoehn published a rating system for Parkinson’s disease in the journal Neurology. It involves 5 stages, ranging from unilateral symptoms but no functional disability (stage 1) to confinement to wheel chair (stage 5). Since then, a modified Hoehn and Yahr scale has been proposed with the addition of stages 1.5 and 2.5 in order to help better describe the intermediate periods of the disease.

Perfecting the use of L-dopa as a treatment for Parkinson’s disease:
In 1968, Greek-American scientist George Cotzias reported dramatic effects on people with Parkinson’s disease using oral L-dopa. The results were published in the New England Journal of Medicine. and L-dopa becomes a therapeutic reality with the Food and Drug Administration (FDA) approving the drug for use in Parkinson’s disease in 1970. Cotzias and his colleagues were also the first to describe L-dopa–induced dyskinesias.

“Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.” Marie Curie

1972-1997, Milestones in Parkinson’s Disease Research and Discovery (Part 1c: Historical):

Levodopa + AADC inhibitors (carbidopa or benserazide:
 When given alone levodopa is broken down to dopamine in the bloodstream, which leads to some detrimental side effects.  By including an aromatic amino acid decarboxylase (AADC) inhibitor with levodopa allows the levodopa to get to the blood-brain barrier in greater amounts for better utilization by the neurons. In the U.S., the AADC inhibitor of choice is carbidopa and in other countries it’s benserazide.

The discovery of dopamine agonists:
Dopamine agonists are ‘mimics’ of dopamine that pass through the blood brain barrier to interact with target dopamine receptors. Since the mid-1970’s, dopamine agonists are often the first medication given most people to treat their Parkinson’s; furthermore, they can be used in conjunction with levodopa/carbidopa. The most commonly prescribed dopamine agonists in the U.S. are Ropinirole (Requip®), Pramipexole (Mirapex®), and Rotigotine (Neupro® patch). There are some challenging side effects of dopamine agonists including compulsive behavior (e.g., gambling and hypersexuality),  orthostatic hypotension, and hallucination.

The clinical use of MAO-B inhibitors:
In the late-1970’s, monoamine oxidase-B (MAO-B) inhibitors were created to block an enzyme in the brain that breaks down levodopa. MAO-B inhibitors have a modest effect in suppressing the symptoms of Parkinson’s.  Thus, one of the functions of MAO-B inhibitors is to prolong the half-life of levodopa to facilitate its use in the brain.  Very recently in clinical trials, it’s been shown that MAO-B inhibitors have some neuroprotective effect when used long-term.  The most widely used MAO-B inhibitors in the U.S. include Rasagiline (Azilect®) and Selegiline (Eldepryl® and Zelpar®); MAO-B inhibitors may reduce “off” time and extend “on” time of levodopa.

Fetal Cell transplantation:
After successful preclinical experiments in rodents, a team of researchers in Sweden, led by Anders Bjorklund and Olle Lindvall, began the first clinical trials of fetal cell transplantation for Parkinson’s disease. These studies involved taking embryonic dopamine cells and injecting them into the brains of people with Parkinson’s disease. The cells then matured and replaced the cells that had been lost during the progression of the disease.

The discovery of MPTP:
In July of 1982, Dr. J. William Langston of the Santa Clara Valley Medical Center in San Jose (California) was confronted with a group of heroin addicts who were completely immobile. A quick investigation demonstrated that the ‘frozen addicts’ had injected themselves with a synthetic heroin that had not been prepared correctly. The heroin contained a chemical called MPTP, which when injected into the body rapidly kills dopamine cells. This discovery provided the research community with a new tool for modeling Parkinson’s disease.

LSVT LOUD®:
LSVT stands for Lee Silverman Voice Treatment for use by speech pathologists; she was the first patient treated by this innovative therapeutic technique in 1985.   LSVT LOUD® was one of the first treatment strategies used for boosting the voice and sound levels of patients with Parkinson’s.   It is set up to be one hour per day for four days per week for four weeks of treatment, and it’s typically very effective in boosting volume and clarity of someone’s voice. LSVT LOUD® led to LSVT BIG®, developed by Dr. Becky Farley and others and it focused on improving movement, mobility, stiffness and stability in Parkinson’s.

Deep-brain stimulation (DBS) surgery becomes a treatment for Parkinson’s disease:
DBS is a surgical procedure used to treat some of the disabling neurological symptoms of Parkinson’s when drug therapy has failed to help the patient’s tremor, rigidity, stiffness, slowed movement, and walking problems.  There are three components in DBS surgery, the electrode, the extension from the electrode to the neurostimulator, which is also called the battery pack. The subthalamic nucleus and the globus pallidus are FDA-approved target sites in the brain for stimulation by the electrode. Although most patients still need to take medication after DBS, many patients experience considerable reduction of their  symptoms and are able to greatly reduce their medications.

“Imagination will often carry us to worlds that never were. But without it we go nowhere.” Carl Sagan

1997-2006, Milestones in Parkinson’s Disease Research and Discovery (Part 1d: Historical):

Slide4

Alpha synuclein becomes the first gene associated with familial cases of Parkinson’s disease and its protein is found in Lewy bodies:
In 1997, a group of researchers at the National institute of Health led by Robert Nussbaum reported the first genetic aberration linked to Parkinson’s disease. They had analyzed DNA from a large Italian family and some Greek familial cases of Parkinson’s disease.

The gene Parkin becomes the first gene associated with juvenile Parkinson’s disease:
The gene Parkin provides the instructions for producing a protein that is involved with removing rubbish from within a cell. In 1998, a group of Japanese scientists identified mutations in this gene that resulted in affected individuals being vulnerable to developing a very young onset (juvenile) version of Parkinson’s disease.

The first use of PET scan brain imaging for Parkinson’s disease:
Using the injection of a small amount of radioactive material (known as a tracer), the level of dopamine present in an area of the brain called the striatum could be determined in a live human being. Given that amount of dopamine in the striatum decreases over time in Parkinson’s disease, this method of brain scanning represented a useful diagnostic aid and method of potentially tracking the condition.

The launch of Michael J Fox Foundation:
In 1991, actor Michael J Fox was diagnosed with young-onset Parkinson’s disease at 29 years of age. Upon disclosing his condition in 1998, he committed himself to the campaign for increased Parkinson’s research. Founded on the 31st October, 2000, the Michael J Fox Foundation has funded more than $700 million in Parkinson’s disease research, representing one of the largest non-governmental sources of funding for Parkinson’s disease.

The Braak Staging of Parkinson’s pathology:
In 2003, German neuroanatomist Heiko Braak and colleagues presented a new theory of how Parkinson’s disease spreads based on the post mortem analysis of hundreds of brains from people who had died with Parkinson’s disease. Braak proposed a 6 stage theory, involving the disease spreading from the brain stem (at the top of the spinal cord) up into the brain and finally into the cortex.

The gene DJ1 is linked to early onset PD:
DJ1 (also known as PARK7) is a protein that inhibits the aggregation of Parkinson’s disease-associated protein alpha synuclein. In 2003, researchers discovered mutations in the DJ1 gene that made people vulnerable to a early-onset form of Parkinson’s disease.

The first GDNF clinical trial indicates neuroprotection in people with Parkinson’s disease:
A small open-label clinical study involving the direct delivery of the chemical Glial cell-derived neurotrophic factor (GDNF) into the brains of people with Parkinson’s disease indicated that neuroprotection. The subjects involved in the study exhibited positive responses to the treatment and postmortem analysis of one subjects brain indicated improvements in the brain.

The genes Pink1 and LRRK2 are associated with early onset PD:
Early onset Parkinson’s is defined by age of onset between 20 and 40 years of age, and it accounts for <10% of all patients with Parkinson’s.  Genetic studies are finding a causal association for Parkinson’s with five genes: α-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and Leucine-rich repeat kinase 2 (LRRK2). However it happens, and at whatever age it occurs, there is no doubt that genetics and environment combine together to contribute to the development of Parkinson’s.

The discovery of induced pluripotent stem (IPS) cells:
In 2006, Japanese researchers demonstrated that it was possible to take skin cells and genetically reverse engineer them into a more primitive state – similar to that of a stem cell. This amazing achievement involved a fully mature cell being taken back to a more immature state, allowing it to be subsequently differentiated into any type of cell. This research resulted in the discoverer, Shinya Yamanaka being awarded the 2012 Nobel prize for Physiology or Medicine.

“Science is organized knowledge. Wisdom is organized life.” Immanuel Kant

2007-2016, Milestones in Parkinson’s Disease Research and Discovery (Part 1e: Historical):

Slide5

The introduction of the MDS-UPDRS revised rating scale:
The Movement Disorder Society (MDS) unified Parkinson’s disease rating scale (UPDRS) was introduced in 2007 to address two limitations of the previous scaling system, namely a lack of consistency among subscales and the low emphasis on the nonmotor features. It is now the most commonly used scale in the clinical study of Parkinson’s disease.

The discovery of Lewy bodies in transplanted dopamine cells:
Postmortem analysis of the brains of people with Parkinson’s disease who had fetal cell transplantation surgery in the 1980-1990s demonstrated that Lewy bodies are present in the transplanted dopamine cells. This discovery (made by three independent research groups) suggests that Parkinson’s disease can spread from unhealthy cells to healthy cells. This finding indicates a ‘prion-like’ spread of the condition.

SNCA, MAPT and LRRK2 are risk genes for idiopathic Parkinson’s disease:
Our understanding of the genetics of Parkinson’s is rapidly expanding. There is recent evidence of multiple genes linked to an increase the risk of idiopathic Parkinson’s. Interestingly, microtubule-associated protein tau (MAPT) is involved in microtubule assembly and stabilization, and it can complex with alpha-synuclein (SNCA).  Future therapies are focusing on  the reduction and clearance of alpha-synuclein and inhibition of Lrrk2 kinase activity.

 IPS derived dopamine neurons from people with Parkinson’s disease:
The ability to generate dopamine cells from skin cells derived from a person with Parkinson’s disease represents not only a tremendous research tool, but also opens the door to more personalized treatments of suffers. Induced pluripotent stem (IPS) cells have opened new doors for researchers and now that we can generate dopamine cells from people with Parkinson’s disease exciting opportunities are suddenly possible.

Neuroprotective effect of exercise in rodent Parkinson’s disease models:
Exercise has been shown to be both neuroprotective and neurorestorative in animal models of Parkinson’s. Exercise promotes an anti-inflammatory microenvironment in the mouse/rat brain (this is but one example of the physiological influence of exercise in the brain), which helps to reduce dopaminergic cell death.  Taking note of these extensive and convincing model system results, many human studies studying exercise in Parkinson’s are now also finding positive benefits from strenuous and regular exercise to better manage the complications of Parkinson’s.

Transeuro cell transplantation trial begins:
In 2010, a European research consortium began a clinical study with the principal objective of developing an efficient and safe treatment methodology fetal cell transplantation in people with Parkinson’s disease. The trial is ongoing and the subjects will be followed up long term to determine if the transplantation can slow or reverse the features of Parkinson’s disease.

Successful preclinical testing of dopamine neurons from embryonic stem cells:
Scientists in Sweden and New York have successfully generated dopamine neurons from human embryonic stem cells that can be successfully transplanted into animal models of Parkinson’s disease. Not only do the cells survive, but they also correct the motor deficits that the animals exhibit. Efforts are now being made to begin clinical trials in 2018.

Microbiome of the gut influences Parkinson’s disease:
Several research groups have found the Parkinson’s disease-associated protein alpha synuclein in the lining of the gut, suggesting that the intestinal system may be one of the starting points for Parkinson’s disease. In 2016, researchers found that the bacteria in the stomachs of people with Parkinson’s disease is different to normal healthy individuals. In addition, experiments in mice indicated that the bacteria in the gut can influence the healthy of the brain, providing further evidence supporting a role for the gut in the development of Parkinson’s disease.

“Any fool can know. The point is to understand.” Albert Einstein

2016-2017, Milestones in Parkinson’s Disease Research and Discovery (Part 2: Clinical trials either recently completed or in progress)

Slide6

Safety, Tolerability and Efficacy Assessment of Dynacirc (Isradipine) for PD (STEADY-PD) III trial:
Isradipine is a calcium-channel blocker approved for  treating high blood pressure; however, Isradipine is not approved for treating Parkinson’s. In animal models, Isradipine has been shown to slow the progression of PD by protecting dopaminergic neurons.  This study is enrolling newly diagnosed PD patients not yet in need of symptomatic therapy. Participants will be randomly assigned Isradipine or given a placebo.

Treatment of Parkinson’s Psychosis with Nuplazid:~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 recently approved by the FDA specifically designed to treat Parkinson’s psychosis.

Opicapone (COMT Inhibitor) as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations:
Catechol-O-methyl transferase (COMT) inhibitors prolong the effect of levodopa by blocking its metabolism. COMT inhibitors are used primarily to help with the problem of the ‘wearing-off’ phenomenon associated with levodopa. Opicapone is a novel, once-daily, potent third-generation COMT inhibitor.  It appears to be safer than existing COMT drugs. If approved by the FDA, Opicapone is planned for use in patients with Parkinson’s taking with levodopa who experience wearing-off issues.

Nilotinib (Tasigna® by Novartis) indicates positive results in phase I trial:
Nilotinib is a drug used in the treatment of leukemia. In 2015, it demonstrated beneficial effects in a small phase I clinical trial of Parkinson’s disease. Researchers believe that the drug activates the disposal system of cells, thereby helping to make cells healthier. A phase II trial of this drug to determine how effective it is in Parkinson’s disease is now underway.

ISCO cell transplantation trial begins:
International Stem Cell Corporation is currently conducting a phase I clinical cell transplantation trial at a hospital in Melbourne, Australia. The company is transplanting human parthenogenetic stem cells-derived neural stem cells into the brains of people with Parkinson’s disease. The participants will be assessed over 12 months to determine whether the cells are safe for use in humans.

Neuropore’s alpha-synuclein stabilizer (NPT200-11) passes phase I trial:
Neuropore Therapies is a biotech company testing a compound (NPT200-11) that inhibits and stablises the activity of the Parkinson’s disease-associated protein alpha synuclein. This alpha-synuclein inhibitor has been shown to be safe and well tolerated in humans in a phase I clinical trial and the company is now developing a phase II trial.

mGluR4 PAM  (PXT002331) well tolerated in phase I trial:
Prexton Therapeutics recently announced positive phase I clinical trial results for their lead drug, PXT002331, which is the first drug of its kind to be tested in Parkinson’s disease. PXT002331 is a mGluR4 PAM – this is a class of drug that reduces the level of inhibition in the brain. In Parkinson’s disease there is an increase in inhibition in the brain, resulting in difficulties with initiating movements. Phase II clinical trials to determine efficacy are now underway.

Initial results of Bristol GDNF trial indicate no effect:
Following remarkable results in a small phase I clinical study, the recent history of the neuroprotective chemical GDNF has been less than stellar. A subsequent phase II trial demonstrated no difference between GDNF and a placebo control, and now a second phase II trial in the UK city of Bristol has reported initial results also indicating no effect. Given the initial excitement that surrounded GDNF, this result has been difficult to digest. Additional drugs that behave in a similar fashion to GDNF are now being tested in the clinic.

Immunotherapies proves safe in phase I trials (AFFiRis & Prothena):
Immunotherapy is a treatment approach which strengthens the body’s own immune system. Several companies (particularly ‘AFFiRis’ in Austria and ‘Prothena’ in the USA) are now conducting clinical trials using treatments that encourage the immune system to target the Parkinson’s disease-associated protein alpha synuclein. Both companies have reported positive phase I results indicating the treatments are well tolerable in humans, and phase II trials are now underway.

Living Cell Technologies Limited continue Phase II trial of NTCELLA New Zealand company called Living Cell Technologies Limited have been given permission to continue their phase II clincial trial of their product NTCELL, which is a tiny capsule that contains cells which release supportive nutrients when implanted in the brain. The implanted participants will be blindly assessed for 26 weeks, and if the study is successful, the company will “apply for provisional consent to treat paying patients in New Zealand…in 2017”.

MAO-B inhibitors shown to be neuroprotective:
MAO-B inhibitors block/slow the break down of the chemical dopamine. Their use in Parkinson’s disease allows for more dopamine to be present in the brain. Recently, several longitudinal studies have indicated that this class of drugs may also be having a neuroprotective effect.

Inhalable form of L-dopa:
Many people with Parkinson’s disease have issues with swallowing. This makes taking their medication in pill form problematic. Luckily, a new inhalable form of L-dopa will shortly become available following recent positive Phase III clinical trial results, which demonstrated a statistically significant improvements in motor function for people with Parkinson’s disease during OFF periods.

Exenatide trial results expected:
Exenatide is a drug that is used in the treatment of diabetes. It has also demonstrated beneficial effects in preclinical models of Parkinson’s disease, as well as an open-label clinical study over a 14 month period. Interestingly, in a two year follow-up study of that clinical trial – conducted 12 months after the patients stopped receiving Exenatide – the researchers found that patients previously exposed to Exenatide demonstrated significant improvements compared to how they were at the start of the study. There is currently a placebo-controlled, double blind phase II clinical trial being conducted and the results should be reported before the end of 2017.

“This is where it all begins. Everything starts here, today.” David Nicholls

A personal reflection:
In my adult life as a scientist, I’ve studied the world of hematology and how your blood clots.   And as a lifelong medical educator, I’ve taught the principles of biomedical science/hematology/oncology/immunology.   But this thing with Parkinson’s,  this for the rest of your life disorder is still relatively new in my life-line. Making this historical timeline was very educational for me; I learned a tremendous amount of information about this disease.  This timeline would not exist without the help and guidance of Simon my friend in Cambridge, England. He has his own blog entitled the Science of Parkinson’s.  Simon went out of his way to help plan and expedite this calendar of Parkinson’s history; I am most thankful for his participation.

“I’m going to be totally honest with you. Dealing with a diagnosis of Parkinson’s is not easy and there is no one, single technique that will ease the pain and no magic pill that will miraculously enable you to cope with it. However … I sincerely hope that you are able to come to terms with the diagnosis and perhaps even come to view it as a positive life-changing experience.” John Baxter

Cover photo credit: http://www.hoasaigon.com.vn/kcfinder/upload/images/tu-van-tang-hoa-chuc-mung-ngay-10-10-cho-nhung-nguoi-phu-nu-than-yeu-14.jp

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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.

17.03.20b.PD_Drugs_Interactions

“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 ‘ClinicalTrials.gov’, 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: https://img1.10bestmedia.com/Images/Photos/304499/Pier-orange-sky-compressed_54_990x660.jpg

Dopamine neurons for the drawing wermodified from http://www.utsa.edu/today/images/graphics/dopamine.jpg

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