Category Archives: Parkinson’s Disease

Understanding The Positive Health Benefits of Gratitude

“If the only prayer you ever say in your entire life is ‘thank you’, it will be enough.” Medieval German Theologian Meister Eckhart

“The smallest act of kindness is worth more than the greatest intention.” Khalil Gibran.

Preface: Gratitude is good for you. The Roman philosopher Seneca said, “Nothing is more honorable than a grateful heart.” The Roman senator Cicero remarked, “Gratitude is not only the greatest of virtues but the parent of all others.” Recognize the health benefits of being grateful.  Why? Gratitude will lead you to the fountain of hope; it is good for your heart, soul, mind, and practicing gratitude will be beneficial for your life with Parkinson’s.

Introduction: In the backdrop of having a chronic disorder like Parkinson’s disease, it is easy to get trapped and driven down emotionally from its daily burden. Life happens and we are constantly making micro- and macro-decisions, big and small changes in direction, and it seems to me the list grows with time. Today’s post is centered on gratitude, not to complicate your life, but as a reminder that being thankful can improve your health all on its own.

“Develop an attitude of gratitude, and give thanks for everything that happens to you, knowing that every step forward is a step toward achieving something bigger and better than your current situation.” Brian Tracy

Gratitude Defined: [grat·i·tudeˈɡradəˌt(y)o͞od/] Gratitude is from the Latin word gratus, meaning “pleasing” or “thankful,” Words from the Latin gratus have something to do with being pleasing or being thankful. To feel grateful is to feel thankful for something. Gratitude is a feeling of thankfulness (Merriam-Webster). Thank you in several languages is shown below (image credit).

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“No duty is more urgent than that of returning thanks.” James Allen

Studies on Gratitude and Health: Doing a PubMed search for “Gratitude” reveals >1000 papers/chapters/books; searching for “gratitude and health” shows >500 citations.  Outside of PubMed, there are numerous reviews and magazine/newspaper/journal articles describing the health benefits of being thankful (having gratitude).  In the end, I will list several for your further viewing/reading. Here are some highlights linking gratitude and a better life.

  • Blessings vs. Burdens- In 2003, Emmons and McCullough published a landmark study of gratitude and well being entitled “Counting Blessings Versus Burdens: An Experimental Investigation of Gratitude and Subjective Well-being in Daily Life”.  They described 3 experiments, two groups were healthy college-aged students and the third group was adults with various neuromuscular disorders.  Within each separate study, some subjects were asked to maintain a journal on a weekly basis for 10 weeks, and others on a daily basis for 2 or 3 weeks.  They all kept records of both positive and negative effects they had experienced; including their behavior coping with these events (health behavior and physical symptoms), and their overall appraisal of life.  Subgroups from each study were asked to focus their journal entries on different things: (Group A) this group recorded things for which they were grateful (they were “counting their blessings”); (Group B) this group recorded things they found irritating and/or annoying (they were “counting their burdens”); and (Group C) this group recorded things that had a major impact on them.  After compiling the data from the 3 experiments, two trends stood out. (1) The participants from ‘Group A’, those recording things for which they were ”grateful’, showed much higher levels of well-being compared to Groups ‘B’ and ‘C’; and this was particularly evident when compared to those recording events that were ‘annoying or irritating’. (2) The positive effects of gratitude in the 10 week study, compared to the 2 or 3 week studies, showed not only better well-being; these participants also showed social and physical benefits.
  • Feeling Happy- In a separate study from 2002, McCullough et al. reported that recording your blessings on a regular basis was linked with increased happiness. In a separate study, Kurtz et al. (2008) showed that this feeling of happiness through gratitude was sustained for several months.
  • Optimism– A study by Overwalle et al. (1995) found a positive link between the ability to express gratitude and the feeling of well-being; suggesting these individuals had an improved/optimistic outlook of their future.
  • Strengthening Bonds and Building Relationships- The link of happiness from gratitude was shown to strengthen bonds, enable friendships, and support social networks.  The results from Reynolds (2008) showed that by practicing gratitude, participants felt more cared for/loved by others.
  • Mapping Neural Networks of Gratitude- In a 2015 paper entitled “Neural correlates of gratitude”, Fox et al. used magnetic resonance imaging (MRI) to map the effect of gratitude in volunteers. They tested a hypothesis that gratitude activity would be linked to brain regions associated with moral cognition, value judgment and theory of mind. Their results showed that gratitude was correlated with brain activity in the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC), which supported their hypothesis (see drawing below).

18.04.12.ACC_mPFC_Thalamus.

“Let us be grateful to people who make us happy.” Marcel Proust

 Linking Gratitude to the Anterior Cingulate Cortex and Basal Ganglia:  The anterior cingulate cortex (ACC) can be described as a ‘neural network interface’ between emotion, sensation, and action. The ACC is linked anatomically with brain areas associated with each of these functions. An important interaction of the ACC is highlighted by its reciprocal connections to the reward centers of the brain, which includes the orbitofrontal cortex, insula, and the basal ganglia. Thus, the ACC is a target for the dopamine-expressing neurons from the substantia nigra (part of the basal ganglia; see figure below).  Understanding the reward of gratitude within the brain has given us an appreciation to what leads to a healthier and happier self. To further augment the benefits of gratitude, we enlist neurotransmitters (serotonin and dopamine):

serotonin.A Squeeze of Serotonin-  Serotonin is an elixir that boosts our mood, enhances will-power and eliminates self-doubt. The anterior cingulate cortex (ACC)  releases serotonin (i) when we write about gratitude and (ii) when we reflect about the positives in our lives (and our work).

dopamine.A Drop of Dopamine- Dopamine makes us feel good. With respect to practicing gratitude, we release dopamine (from the substantia nigra in the basal ganglia) (i) when we express gratitude for what’s good in our lives and (ii) when we offer gratitude for someone who has helped us thrive at life/work,

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“We must find time to stop and thank the people who make a difference in our lives.” John F. Kennedy

Gratitude Promotes the “4H Club” That Includes Happy, Healthy, Heartfelt, and Hopeful: I am neither a psychologist nor a neurologist, but I truly enjoyed reading the Emmons and McCullough (2003) paper described above (“Counting Blessings Versus Burdens: An Experimental Investigation of Gratitude and Subjective Well-being in Daily Life”).  First, it was well-written and easy to follow.  Second, they asked and answered some very important questions linked to gratitude.  Clearly, their work was preceded by other studies; however, their results likely provided a foothold for others to launch their ideas about how gratitude influences the human condition. In summarizing many studies, the folks at Happier Human (What About Happiness?) posted an amazing article entitled “The 31 Benefits of Gratitude You Didn’t Know About: How Gratitude Can Change Your Life” (click here) along with the figure below showing the huge overall impact of gratitude on human happiness (credit).

Benefits-of-Gratitude5

Remember, I am not a psychologist.  However, I felt that four major themes could be used to represent the positive impact of gratitude. Borrowing from the ‘4H Club’ name, the benefits of gratitude could make someone Happy, Healthy, Heartfelt, and Hopeful (see Figure below). And there are numerous studies to support the positive impact of gratitude on these four aspects of life (see references cited at the end).

Screenshot 2018-04-10 23.49.01

“To give thanks in solitude is enough. Thanksgiving has wings and goes where it must go. Your prayer knows much more about it than you do.” Victor Hugo

Pursuing Happiness Through Gratitude and How to Achieve it: The best strategy for expressing gratitude requires your investment of time to create and maintain a gratitude-journal.  The idea is for your gratitude-journal to have short statements where you describe your gratitude, you reflect on your positive life-events, you give thanks to others, you think-ponder deeply, and write 3-5 things per time and you decide on the frequency (every few days, more or less, but you decide).   Here are some examples:

  • I hit golf balls at the driving range 2 days in a row this week, what fun;
  • Spring weather finally has arrived, it waited ’til now but that’s OK;
  • Got 6.5 hours of sleep one night last weekend (yay!);
  • A reader of the blog wrote to tell me how much he appreciates and values my blog posts [and that he was my biggest fan (thank you so much)];
  • I’ve enjoyed teaching my undergraduate class this semester;
  • Thankful for all of my favorite Physical Therapists who inspire me to exercise and to stay healthy (“Keeping your body healthy is an expression of gratitude to the whole cosmos — the trees, the clouds, everything.” Nhat Hanh);
  • So very proud of CJ for presenting her poster this week at the University Undergraduate Student Research Day;
  • Very thankful for the incredible help Marissa and Shelby have provided me as Teaching Assistants this semester;
  • Look forward to seeing my sisters in the near future;
  • Having lunch tomorrow with 2 former students from my undergraduate class, and this week I went out for lunch with the current class (I learn much from these events);
  • Received an amazing thank-you note from a former student;
  • Very fortunate to have Susan in my life, look forward to catching up soon.

“For each new morning with its light, For rest and shelter of the night, For health and food, for love and friends… Feeling gratitude and not expressing it is like wrapping a present and not giving it.” William Arthur Ward

Benefits of Gratitude and Health in the Presence of Parkinson’s: The anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) of the brain are the key components that respond to gratitude. There is no doubt that people-with-Parkinson’s experience the benefits of gratitude and the 4H’s (Happy, Healthy, Heartfelt, and Hopeful).  However, the ACC communicates with the basal ganglia, which implies some role for dopamine. Thus, we must believe we still synthesize enough dopamine to realize the positive effects from gratitude (well, this is what I believe).

In closing, as I said at the start, I am convinced that gratitude will lead you to the fountain of hope; it is good for your heart, soul, mind, and practicing gratitude will be beneficial for your life with Parkinson’s. May you continue to be thankful. May the positive effects from gratitude provide you a constant source of happiness and good health that are reinforced by heartfelt feelings and hope for years to come.

“Thanks are the highest form of thought.” Gilbert K Chesterton

References For Your Further Reading:
Emmons RA, McCullough ME. Counting blessings versus burdens: an experimental investigation of gratitude and subjective well-being in daily life. Journal of personality and social psychology. 2003;84(2):377-89. Epub 2003/02/15. PubMed PMID: 12585811.

Fox GR, Kaplan J, Damasio H, Damasio A. Neural correlates of gratitude. Frontiers in psychology. 2015;6:1491. Epub 2015/10/21. doi: 10.3389/fpsyg.2015.01491. PubMed PMID: 26483740; PMCID: PMC4588123.

The 31 Benefits of Gratitude You Didn’t Know About: How Gratitude Can Change Your Life (click here).

McCullough ME, Emmons RA, Tsang J. The grateful disposition: a conceptual and empirical typology. J Pers Soc Psychol. 2002;82:112–127.

Kurtz JL, Lyubomirsky S. Towards a durable happiness. In: Lopez SJ, Rettew JG, eds. The Positive Psychology Perspective Series. Vol 4. West-port, CT: Greenwood Publishing Group; 2008:21–36.

Overwalle FV, Mervielde I, De Schuyter J. Structural modeling of the relationships between attributional dimensions, emotions, and performance of college freshmen. Cognition Emotion. 1995;9:59–85.

7 Surprising Health Benefits of Gratitude (click here).

Martins A, Ramalho N, Morin E. A comprehensive meta-analysis of the relationship between Emotional Intelligence and health. Personality and Individual Differences. 2010;49(6):554-64. doi: https://doi.org/10.1016/j.paid.2010.05.029.

Alspach G. Extending the tradition of giving thanks recognizing the health benefits of gratitude. Crit Care Nurse. 2009;29(6):12-8. doi: 10.4037/ccn2009331. PubMed PMID: 19952333.

Emmons RA, Crumpler CA. Gratitude as a Human Strength: Appraising the Evidence. Journal of Social and Clinical Psychology. 2000;19(1):56-69. doi: 10.1521/jscp.2000.19.1.56.

Ma LK, Tunney RJ, Ferguson E. Does gratitude enhance prosociality?: A meta-analytic review. Psychological bulletin. 2017;143(6):601-35. Epub 2017/04/14. doi: 10.1037/bul0000103. PubMed PMID: 28406659.

7 Ways to Boost Your Gratitude (click here).

Reynolds DK. Naikan Psychotherapy: Meditation for Self-Development. Chicago, IL: University of Chicago Press; 1983.

O’Connell BH, O’Shea D, Gallagher S. Feeling Thanks and Saying Thanks: A Randomized Controlled Trial Examining If and How Socially Oriented Gratitude Journals Work. Journal of clinical psychology. 2017;73(10):1280-300. Epub 2017/03/07. doi: 10.1002/jclp.22469. PubMed PMID: 28263399.

Sirois FM, Wood AM. Gratitude uniquely predicts lower depression in chronic illness populations: A longitudinal study of inflammatory bowel disease and arthritis. Health psychology : official journal of the Division of Health Psychology, American Psychological Association. 2017;36(2):122-32. Epub 2016/10/28. doi: 10.1037/hea0000436. PubMed PMID: 27786519.

“Gratitude unlocks the fullness of life. It turns what we have into enough, and more. It turns denial into acceptance, chaos to order, confusion to clarity. It can turn a meal into a feast, a house into a home, a stranger into a friend.” Melody Beattie

 Cover photo credit: https://visitsrilanka.com/news/its-blooming-spring-22-great-uk-walks/

2018 Parkinson’s Awareness Month and 65 Quotes to Support Your Life With Parkinson’s

“Don’t give up. Don’t ever give up.” Jim Valvano

“Courage starts with showing up and letting ourselves be seen.” Brené Brown

Parkinson’s disease Awareness Month: Parkinson’s awareness month is exactly that.  You simply start by making people around you familiar with this disorder.  And you can help others learn more about this neurodegenerative disease.

Description of Parkinson’s disease: Instead of the usual written narrative, here are a couple of video presentations.

NPFiconFor further information also see: Understanding Parkinson’s.

 65* Quotes on Adversity, Hope, Journey, Life, and Persistence to Help You During the ‘Off-moments’ and to Remind You to Never Give up (*Why 65? My age later this year):

  1. “To me, hope is informed optimism.” Michael J. Fox
  2. “The truth is that on most days, there comes a point where I literally can’t stop laughing at my own symptoms.” Michael J. Fox
  3. “The strongest people are not those who show strength in front of us but those who win battles we know nothing about.” Anonymous

  4. “Behind every chronic illness is just a person trying to find their way in the world. We want to find love and be loved and be happy just like you. We want to be successful and do something that matters. We’re just dealing with unwanted limitations in our hero’s journey.” Glenn Schweitzer
  5. “Friendship is the hardest thing in the world to explain. It’s not something you learn in school. But if you haven’t learned the meaning of friendship, you really haven’t learned anything.”Muhammad Ali
  6. “Impossible is just a big word thrown around by small men who find it easier to live in the world they’ve been given than to explore the power they have to change it. Impossible is not a fact. It’s an opinion. Impossible is not a declaration. It’s a dare. Impossible is potential. Impossible is temporary. Impossible is nothing.” Muhammad Ali
  7. “Sometimes the smallest step in the right direction ends up being the biggest step of your life. Tip Toe if you must, but take a step.” Naeem Callaway
  8. “When the unthinkable happens, the lighthouse is hope. Once we choose hope, everything is possible.”  Christopher Reeve
  9. “Believe in yourself and all that you are. Know that there is something inside of you that is greater than any obstacle.” Christian D. Larson
  10. “You shouldn’t focus on why you can’t do something, which is what most people do. You should focus on why perhaps you can, and be one of the exceptions.” Steve Case
  11. “Hope begins in the dark, the stubborn hope that if you just show up and try to do the right thing, the dawn will come. You wait and watch and work; you don’t give up.” Anne Lamott
  12. “You are strong when you know your weaknesses. You are beautiful when you appreciate your flaws. You are wise when you learn from your mistakes.”  unknown
  13. “Champions aren’t made in gyms. Champions are made from something they have deep inside them—a desire, a dream, a vision. They have to have last-minute stamina, they have to be a little faster, they have to have the skill and the will. But the will must be stronger than the skill.”Muhammad Ali
  14. “The strongest people I’ve met have not been given an easier life. They’ve learned to create strength and happiness from dark places.”  Kristen Butler
  15. “You either get bitter or you get better. It’s that simple. You either take what has been dealt to you and allow it to make you a better person, or you allow it to tear you down. The choice does not belong to fate, it belongs to you.” Josh Shipp
  16. “It’s not selfish to love yourself, take care of yourself, and to make your happiness a priority.” Mandy Hale
  17. “Live to inspire, and one day people will say, because of you, I didn’t give up” unknown
  18. Some days are better, some days are worse. Look for the blessing instead of the curse. Be positive, stay strong, and get enough rest. You can’t do it all, but you can do your best. Doe Zantamata
  19. “I can’t tell you when, but I can promise you it will get better, it will get easier, and it will all be worthwhile. Just promise me you won’t ever give up.” unknown
  20. “Maybe life isn’t about avoiding the bruises. Maybe it’s about collecting the scars to prove that we showed up for it.” Hannah Brecher
  21. “We are stronger in the places we have been broken.” Ernest Hemingway
  22. “Just put one foot in front of the other.”  Austin Peck
  23. “Coming together is a beginning; keeping together is progress; working together is success.”  Henry Ford
  24. “Alone we can do so little; together we can do so much.”  Helen Keller
  25. “If everyone is moving forward together, then success takes care of itself.”  Henry Ford
  26. “We keep moving forward, opening new doors, and doing new things, because we’re curious and curiosity keeps leading us down new paths.” Walt Disney
  27. “I find that the best way to do things is to constantly move forward and to never doubt anything and keep moving forward, if you make a mistake say you made a mistake.”  John Frusciante
  28. “Don’t dwell on what went wrong. / Instead, focus on what to do next. / Spend your energies on moving forward / toward finding the answer.” Denis Waitley
  29. “If you stumble, make it part of the dance.” unknown
  30. “If opening your eyes, or getting out of bed, or holding a spoon, or combing your hair is the daunting Mount Everest you climb today, that is okay.” Carmen Ambrosio
  31. “Please be patient with me. Sometimes when I’m quiet, it’s because I need to figure myself out. It’s not because I don’t want to talk. Sometimes there are no words for my thoughts.”  Kamla Bolaños
  32. “What would the hero of your life’s movie do right now? Do that!” Joe Rogan
  33. “Inspirations knock and hang around for a while and wait for some kind of response, which is the beginning of a creative act.” Thomas Moore
  34. “What you do makes a difference, and you have to decide what kind of difference you want to make.” Jane Goodall
  35. “What’s meant to be will always find a way” Trisha Yearwood
  36. “Do not pray for an easy life, pray for the strength to endure a difficult one.”  Bruce Lee
  37. “One who gains strength by overcoming obstacles possesses the only strength which can overcome adversity.” Albert Schweitzer
  38. “When we long for life without difficulties, remind us that oaks grow strong in contrary winds and diamonds are made under pressure.” Peter Marshall
  39. “Ask yourself what problem you have right now. Not next year, tomorrow or five minutes from now. You can always cope with the now, but you can never cope with the future. Nor do you have to. The answer, the strength and the right action will be there when you need it. Not before or after.” Eckhart Tolle
  40. “Pain is temporary. It may last a minute, or an hour, or a day, or a year, but eventually it will subside and something else will take its place. If I quit, however, it lasts forever.” Lance Armstrong
  41. “If you are depressed you are living in the past.
    If you are anxious you are living in the future.
    If you are at peace you are living in the present.”
    Lao Tzu
  42. “To die is poignantly bitter, but the idea of having to die without having lived is unbearable.” Erich Fromm
  43. “Sometimes the hardest part isn’t letting go but rather learning to start over.” Nicole Sobon
  44. “You do not need to know precisely what is happening, or exactly where it is all going. What you need is to recognize the possibilities and challenges offered by the present moment, and to embrace them with courage, faith and hope.” Thomas Merton
  45. “The journey of a thousand miles begins with one step.” Lao Tzu
  46. “Everyone is handed adversity in life. No one’s journey is easy. It’s how they handle it that makes people unique.” Kevin Conroy
  47. “You gain strength, courage, and confidence by every experience in which you really stop to look fear in the face. You are able to say to yourself, ‘I lived through this horror. I can take the next thing that comes along.” Eleanor Roosevelt
  48. “Hope is faith holding out its hand in the dark.” George Iles
  49. “Every day you may make progress. Every step may be fruitful. Yet there will stretch out before you an ever-lengthening, ever-ascending, ever-improving path. You know you will never get to the end of the journey. But this, so far from discouraging, only adds to the joy and glory of the climb.” Winston S. Churchill
  50. “Hope is being able to see that there is light despite all of the darkness.” Desmond Tutu
  51. “Hope is important because it can make the present moment less difficult to bear. If we believe that tomorrow will be better, we can bear a hardship today.” Thich Nhat Hanh
  52. “There is no medicine like hope, no incentive so great, and no tonic so powerful as expectation of something tomorrow.” Orison Swett Marden
  53. “Courage is not having the strength to go on; it is going on when you don’t have the strength. ”Theodore Roosevelt
  54. “The most authentic thing about us is our capacity to create, to overcome, to endure, to transform, to love and to be greater than our suffering.” Ben Okri
  55. “Sometimes you will be in control of your illness and other times you’ll sink into despair, and that’s OK! Freak out, forgive yourself, and try again tomorrow.” Kelly Hemingway
  56. “You may be the only person left who believes in you, but it’s enough. It takes just one star to pierce a universe of darkness. Never give up.” Richelle E. Goodrich
  57. “You can have anything you want if you want it badly enough. You can be anything you want to be, do anything you set out to accomplish if you hold to that desire with singleness of purpose.” Abraham Lincoln
  58. “Whatever you are, be a good one.” Abraham Lincoln
  59. “I know now, after fifty years, that the finding/losing, forgetting/remembering, leaving/returning, never stops. The whole of life is about another chance, and while we are alive, till the very end, there is always another chance.” Jeanette Winterson
  60. “Affliction comes to us, not to make us sad but sober; not to make us sorry but wise.” H.G. Wells
  61. “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.”  Frank C. Church
  62. 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.” Frank C. Church
  63. Today renews your lease on the rest of your life, enjoy it (get up, get out, get going). Today acknowledge your Parkinson’s; give it a nudge, because you are ready for the battle and for life.” Frank C. Church
  64. “The sum total of our health is a complex formula that differs slightly for each one of us.  Those of us with a progressive neurodegenerative disorder like Parkinson’s increases the complexity of this life-equation.” Frank C. Church
  65. “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.” Frank C. Church

“When nothing seems to help, I go and look at a sonecutter hammering away at his rock, perhaps a hundred times without as much as a crack showing in it. Yet at the hundred and first blow it will split in two, and I know it was not that last blow that did it, but all that had gone before.”  Jacob A. Riis

Cover photo credit: https://uspstrackingtool.com/red-tulips-bouquet-of-flowers-wallpaper/

 

Parkinson’s Awareness Month: The Science Behind How Exercise Slows Disease Progression

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

“To enjoy the glow of good health, you must exercise.” Gene Tunney

Précis: For Parkinson’s Awareness Month, let’s begin with an important reminder/statement that “Exercise is medicine for Parkinson’s disease.”  Coming soon in a future blog post I will review the benefits of vigorous exercise in human Parkinson’s.  In today’s blog post, using an established mouse model of Parkinson’s disease and exercise, the recent paper from Wenbo Zhou and collaborators in Aurora, CO will be described. 

The full citation to this open-access paper is as follows: Wenbo Zhou, Jessica Cummiskey Barkow, Curt R. Freed. Running wheel exercise reduces α-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson’s disease. PLOS ONE, 2017; 12 (12): e0190160 DOI: 10.1371/journal.pone.0190160

Screenshot 2018-04-07 10.10.51

“Health is the thing that makes you feel that now is the best time of the year.”Franklin P. Adams

The Neuroprotective Role of Exercise in Parkinson’s, A Quick Look Back: In my own academic career (during the past 30-something years) studying deep-vein thrombosis (hematology) and breast cancer cell migration/invasion (oncology) we used many different types of experimental techniques, specifically: developing protocols to purify blood proteins; three-dimensional molecular modeling; site-directed mutagenesis and expression of recombinant proteins; blood plasma-based model systems; cell-based model systems of cancer cell migration, invasion, and cell signaling; immunohistochemical (pathology) evaluation of human tissues; mouse model systems of cancer cell invasion and metastasis; and mouse model systems of venous thrombosis, aging, and wound healing/repair. I was very fortunate to be able to recruit some truly amazing graduate students and postdoctoral fellows to perform all of these studies.

Likewise, there are a lot of ways to study a disorder like Parkinson’s disease including model cell systems, model rodent systems, and human clinical trials. However, Parkinson’s is not an ‘easy’ human disease to characterize; even with the four Cardinal motor symptoms, we express our disorder slightly differently from one other.  In the past 20-25 years, from reading the literature, much has been learned and advanced with various rodent model systems of Parkinson’s. Studies began in the early 2000’s evaluating the role of exercise in rodent Parkinson’s model systems.  Four such papers (out of many) are highlighted below; with evidence for neuroprotection, neuro-restoration and neuroplasticity. In a 2001 study, Tillerson et al. concluded “These results  suggest that physical therapy may be beneficial in Parkinson’s disease.” Importantly, recent human clinical trials/studies are clearly showing positive results with exercise in Parkinson’s (depending on the study they have shown neuroprotection, improved motor defect and cognitive function gains).

  • Screenshot 2018-04-08 20.51.07Screenshot 2018-04-07 21.30.27Screenshot 2018-04-08 20.48.59Screenshot 2018-04-08 20.46.01

“Take care of your body. It’s the only place you have to live.” Jim Rohn

Highlights and Overview of “Running wheel exercise reduces α-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson’s disease”:

  • Gene mutations that have been found to cause Parkinson’s include α-synuclein, Parkin, UCHL1, DJ-1, PINK1, LRRK2, and VSP35. These mutations result in loss of neuroprotection (e.g., DJ-1 and PINK1), or gain of toxic function (e.g., α-synuclein and LRRK2).
  • The protein α-synuclein is a major component of Lewy bodies that are the signature brain lesions in Parkinson’s. A mouse model that overexpresses human α-synuclein is very similar to the human condition.  The most neurotoxic form of α-synuclein are the α-synuclein oligomers, which implies that preventing α-synuclein aggregation could slow disease progression.
  • The focus of this research was the neuroprotective effects of exercise (running wheel) in mice and quantifying the effect from exercise; they found typically the mice ran >5miles/day.

running

  • They found that one week of running wheel activity led to significantly increased DJ-1 protein concentrations in muscle and plasma in normal mice (compared to mice not running).  Furthermore, using a mouse model with DJ-1 genetically deleted, running wheel performance was much reduced indicating that DJ-1 is important for normal motor activity.
  • They then studied exercise in a mouse model expressing a mutant human form of α-synuclein that is found in all neurons- they wanted to see if exercise could prevent abnormal α-synuclein protein deposition and behavioral decline.
  • Their results showed that motor and cognitive performance were significantly better in exercising animals compared to control mice not allowed to run.
  • They found that the exercising mice had significantly increased levels of DJ-1, Hsp70 and BDNF concentrations and had significantly less α-synuclein aggregation in brain compared to control mice not allowed to run.
  • Interestingly, they also found that blood plasma concentrations of α-synuclein were significantly higher in exercising mice compared to control mice not allowed to run.
  • They conclude that exercise may be neuroprotective. Their results imply that exercise may slow the progression of Parkinson’s disease by preventing α-synuclein aggregation in brain.
  • Below are presentation of interesting results from Figures 4, 5, and 6:

Figure 4 (above) shows that exercise in the aged over-expressing α-synuclein mice had increased levels of DJ-1 (panel B), HSP70 (panel C) and BDNF (panel D) in their brains, and also increased DJ-1 levels in both muscle (panel F) and blood plasma (panel G), compared to non-exercise control mice.

Figure 5 (above) shows that exercise in the aged over-expressing α-synuclein mice had reduced formation of oligomeric α-synuclein (panel C is specific for human α-synuclein protein and panel D is for both mouse and human α-synuclein protein) compared to non-exercise control mice.

Figure 6 (above) shows that exercise in the aged over-expressing α-synuclein mice had increased α-synuclein concentration in blood plasma (panel C is specific for human α-synuclein protein and panel D is for both mouse and human α-synuclein protein) compared to non-exercise control mice.

“I have two doctors, my left leg and my right.” G.M. Trevelyan

Exercise Slows Progression of Parkinson’s: This was both a straightforward and elegant study that gives mechanistic insight into the positive benefits of exercise in Parkinson’s. Here is how it could hopefully be translated from mouse to man: (1) Exercise prevents α-synuclein oligomer accumulation in brain; reduced in brain and increased (monomers and dimers) in blood plasma.  (2) Exercise significantly improved motor and cognitive function.  (3) The benficial effects of exercise is partly related to increased levels of DJ-1, Hsp70 and BDNF, which are neuroprotective substances. (4)  It is not possible to totally define/describe how exercise alters brain function in Parkinson’s when exercise itself produces such widespread systemic changes and benefits.

In conclusion, this study clearly demonstrates the neuroprotective effect of exercise.  It almost seems that exercise made the brain behave like a molecular-sieve to filter out the toxic oligomeric α-synuclein protein and it accumulated in the bloodstream.  Exercise works by slowing the progression of Parkinson’s. 

“If you always put limit on everything you do, physical or anything else. It will spread into your work and into your life. There are no limits. There are only plateaus, and you must not stay there, you must go beyond them.” Bruce Lee

Featured cover image credit:  https://www.pinterest.com/pin/22025485657771738/?lp=true

Neuroprotection with Taurine in a Parkinson’s Model System

“There is no medicine like hope, no incentive so great, and no tonic so powerful as expectation of something tomorrow.” Orison Swett Marden

“Hope sees the invisible, feels the intangible, and achieves the impossible.” Helen Keller

Introduction: Many of us take levodopa/carbidopa for substantial symptomatic relief; however, this dopamine replacement treatment only relieves symptoms without offering either neuroprotection or neuro-restoration. We are still anxiously waiting for the study to be released that announces “We describe a new Parkinson’s compound and we’ve nicknamed it hopeful, helpful, and protective“.   Today’s post will review an interesting paper from Yuning Che and associates in Dalian, China recently published in Cell Death and Disease (open access, click here to download paper).  The ‘hopeful’ neuroprotective compound is the amino sulfonic compound taurine.  Before we get lost in all of the possibilities, let’s discuss the science and see what they describe, ok? First, we begin with some background.

Screenshot 2018-04-02 09.55.23

“I truly believe in positive synergy, that your positive mindset gives you a more hopeful outlook, and belief that you can do something great means you will do something great.” Russell Wilson

Neuroinflammation and Oxidative Stress are Pathological Processes that  Promote the Development of Parkinson’s:   Parkinson’s is a neurodegenerative disorder where we lose dopamine-producing neurons in the mid-brain substantia nigra.   There are several pathological patterns known to contribute to the development of Parkinson’s as highlighted below.  Related to this post is the negative-effect contributed by long-term neuroinflammation and oxidative stress.

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“It’s hope as a decision that makes change possible.” Jim Willis

Macrophages in the Brain are Called Microglia Cells:  In many instances, the body initiates and uses the pro-inflammatory machinery as a host-defense response; in other words, we use it to protect ourselves.  When it gets highjacked and becomes detrimental to be host, we realize the sheer firepower of our inflammatory system.  The good-and-the-bad of inflammation is mediated primarily by the cells named neutrophils (along with the eosinophils and basophils), monocytes and macrophages.  The monocyte leaves the bloodstream and migrates to various organs/tissues where it can ‘mature’ into a macrophage, which is a ‘field commander’ type-of-cell.  Think of a macrophage as a General in the bunker of a battlefield, not only giving detailed marching orders but they are also leading the charging brigade of soldiers.  Macrophages in the brain are named microglia cells .  First, macrophages (microglia cells) are ‘phagocytic’ cells that are capable of engulfing foreign-damaged-invading substances/cells (phagocyte comes from the Greek phagein, “to eat” or “devour”, and “-cyte”, the suffix in biology denoting “cell”).  Second, macrophages (microglia cells) direct the inflammatory response by releasing all kinds of substances that give other inflammatory/immune cells their instructions.  Sometimes these cells and their instructions become bad to the neighboring tissue/organs; in our case, the dopamine-produing neurons in the midbrain.

activated_microgliaMicroglia-mediated neuroinflammation(Figure credit): Various substances initiate contact with resting unstimulated microglia cells.  This ‘activates’ the microglia cell into an cell of considerable fire-power by producing and releasing many substances [nitric oxide (NO), reactive oxygen species (ROS),  and several inflammatory cytokines (e.g., IL-1, IL-6, and  TNF-alpha)]. This collection of pro-inflammatory substances secreted by the activated microglia cells creates a hostile microenvironment that promotes neuronal cell dysfunction and potential death to the cell.

Depending on the need and response of the ‘environmental challenge’, macrophages (microglia cells) can be activated to become either ‘M1’ (focused on becoming a pro-inflammatory) microglia cell or ‘M2’ (transforms into an anti-inflammatory) microglia cell [see Figure below, credit].  In the setting of an invasion or infiltration by microbes, you would want the microglia cell to be activated to a M1 state’ they could attack, engulf and kill the invading microorganism. In this setting, the M1 microglia cell would be protective of you. By contrast, the role of M2 microglia cells would be to turn-off the resultant pro-inflammatory response.  This implies that long-term inflammatory events that promote inappropriate M1 microglia cell activation could lead to dysfunction and even cell/tissue death. This description of appropriate/inapproriate microglia cell activation illustrates the complex nature of these inflammatory cells. What this says is in Parkinson’s, chronic activation to M1 microglia cells could generate a detrimental neuroinflammatory environment able to attack host cells/tissues.

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“It is difficult to say what is impossible, for the dream of yesterday is the hope of today and the reality of tomorrow.” Robert H. Goddard

Taurine: Taurine is an amino sulfonic compound (many erronously use the term amino acid) and it is considered to be a conditionally essential nutritient.  We do not use taurine in the assembly of proteins from genes; however, it participates in several physiological systems.  Taurine is apparently a popular additive/supplement in many different energy drinks.  Both WebMD (click here) and the Mayo Clinic (click here) have posted overviews of taurine and consider it mostly safe.  The structure of taurine is shown below (credit). Taurine is found in the brain, heart, muscle and in many other organs.  Good sources of dietary taurine are animal and fish proteins. An interesting overview for using taurine to stay healthy and to promote longevity has recently been posted (click here). Taurine has many proposed physiological functions that range from neurotransmitter to cell anti-oxidant, from anti-inflammatory to enhancing sports performance.  The ‘problem’ with having a multi-talented substance like taurine is actually studying these diverse functions individually and trying to test them in rigorous scientific studies, which leads us (finally!) to the paper introduced at the beginning.

Taurine.svg

“Hope is the mainspring of life.” Henry L. Stimson

Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization: Here are some key aspects to this  study:

  • It is becoming more evident that neuroinflammation and oxidative stress are likely key participants to the development of Parkinson’s.
  • Surrounding the substantia nigra are a lot of unactivated microglia cells, which when activated to become M1 microglia cells they secrete several cytotoxic compounds that can easily harm or kill dopaminergic-producing neurons.
  • In particular, these neurons are susceptible to ‘injury’ due to their low antioxidant potential, low levels of calcium, increased amounts of iron, and the oxidation-susceptible dopamine.
  • Taurine has been shown in several reports to be a neuromodulating substance, boosting intracellular levels of calcium, anti-oxidant, and anti-inflammatory.
  • A recent report linked motor severity in Parkinson’s to low levels of taurine in blood plasma.
  • The authors tested a hypothesis that the supplementation with exogenous taurine might be neuroprotective in a Parkinson’s model sy\stem.
  • Previous studies have revealed a neuroprotective role for taurine in both glutamate-induced and hypoxic-ischemic brain models.
  • They used a mouse model of Parkinson’s caused by injection with paraquat and maneb [(P + M) a two-pesticide model of Parkinson’s], which showed progressive dopaminergic neurodegenera-
  • tion, gait abnormality and α-synuclein aggregation.
  • Taurine treatment protected the mouse from the detrimental effect of  P + Mu.
  • Their results revealed three effects of taurine in the P + M model of Parkinson’s (i) inhibition of microglia cell activation; (ii) reduced M1 microglia cell polarization; and (iii) reduced activation of cellular NOX2 and nuclear factor-kappa B (NF-κB).

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

Overview of Some of Their Results: Figure 1 presents the effect of P + M to promote a pathological state that resembles Parkinson’s.  Panels 1A and 1B show the loss of dopaminergic neurons by the staining of the brain with an antibody to tyrosine hydroxylase (a major dopaminergic neuron protein) following P + M injection.  Panels !C and 1D show that P + M treatment lead to expression of the toxic olgiometic α-synuclein.  Not shown here, but P + M treatment resulted in displayed abnormal gaits (Figure 2 in the paper). Screenshot 2018-04-05 11.18.39

Taurine protected against P + M-mediated neurotoxicity.  Using the same tests as done in Figure 1 above, taurine preserved neurons even with P + M present (Figure 3 panels A and B) and taurine reduced expression of oligomeric α-synuclein in the presence of P + M (Figure 3 panels C and D).  Not included here, the protective effects of taurine during P + M treatment was partly due to the inhibition of migroglia cell-mediated chronic inflammation.  Furthermore, the ability of microglia cells to become  ‘polarized’ or activated to either M1 (pro-inflammatory) or M2 (anti-inflammatory) was also studied in the presence of taurine plus P + M-treatment.  Both M1 and M2 microglia cells are present in the mid-brain of the mice treated with P + M; interestingly, taurine treatment reduced expression levels of damaging M1 microglia cell products (results not included here).  Finally, two key M1-linked gene products were studied, NOX2 and NF-kB.  They found that taurine was able to reduce expression of both NOX2 and NF-kB, which indicates that taurine blocked these key products important for neuroinflammation (NOX2) and polarization of the M1 microglia cell-type (NF-kB)

Screenshot 2018-04-05 11.37.57

“The present is the ever moving shadow that divides yesterday from tomorrow. In that lies hope.” Frank Lloyd Wright

What do these results show? (1) In an interesting model of Parkinson’s, taurine showed  a potent benefit to the mice; (2) taurine reduced loss of dopamine-producing neurons in P + M mice; (3) taurine reduced oligomeric α-synuclein in P + M mice; (4) taurine treatment reduced neuroinflammation by suppressing M1 microglia cells to suggest a neuroprotectice effect; and finally, (5) taurine reduced expression of both NOX2 and NF-kB,  important genes for microglia cell activation. A similar neuroprotective effect was also found for taurine in an experimental model of Alzheimer’s disease, which resulted in improved coognitive ability. The Parkinson’s model clearly suggests that disease progression by P + M treatment is promoted by chronic neuroinflammation and M1-type microglia cells.  Under the test conditions used, taurine was shown to convincingly reduce dopamine-producing neuronal cell degeneration in the presence of the pesticides P + M.

What do these results suggest? There is still much to learn about taurine. There is much potential to taurine being neuroprotective.  However, there have been other seriously–convincing-positive mouse model results with other compounds that failed miserably in human clinical trials.  The data shown here uses an interesting mouse model of Parkinson’s with a simple yet elegant and solid set of data (that does not appear to be overly interpreted).  Taurine has been shown to be safe in treating other human maladies (diabetes and cardiovascular disease).  The results here are hopeful that taurine could provide neuroprotection in human Parkinson’s. Hopefully, clinical trials will be started somewhere soon to determine the ability of taurine to provide neuroprotection in human Parkinson’s disease.

“Every one of us is called upon, perhaps many times, to start a new life. A frightening diagnosis, a marriage, a move, loss of a job…And onward full-tilt we go, pitched and wrecked and absurdly resolute, driven in spite of everything to make good on a new shore. To be hopeful, to embrace one possibility after another–that is surely the basic instinct…Crying out: High tide! Time to move out into the glorious debris. Time to take this life for what it is.” Barbara Kingsolver

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Living and Working with “HOPE” in the Presence of Parkinson’s

“Life is difficult. This is the great truth, one of the greatest truths-it is a great truth because once we see this truth, we transcend it.” M. Scott Peck

“Life is hard. Life is beautiful. Life is difficult. Life is wonderful.” Kate DiCamillo

Introduction: A student and loyal reader of this blog recently asked “What do I do with all of the advice/tips/suggestion posts from the blog?” My reply was they help me balance out my day-to-day life; especially for work and to protect my time for exercise and time to spend with the significant-people in my life.  I typically print out the 1-page summaries and keep them in a folder, or post them at work, as reminders to what I value.  “What about all of your supportive and descriptive statements about living well with Parkinson’s disease?  I bet your readers of the blog would enjoy having some of your statements compiled like your advice posts, don’t you agree?”  My response was you want me to make some 1-page handouts of my comments? Yes, I could do that. That kind of a handout could help me as well; they could also serve as a roadmap to where the blog has traveled.  Interesting questions/suggestions, thanks for asking them.

“If you don’t know where you are going, you might wind up someplace else.” Yogi Berra

The tenacity of hope: There are 4 broad goals to this blog: i) describe living with Parkinson’s (“Life Lessons“); ii) report emerging medical strategies for treating/managing/curing Parkinson’s (“Medical Education“); iii) support mechanism to anyone with Parkinson’s or any of the neurodegenerative disorders (“Strategy for Living“); and iv) educate by presenting scientific aspects of Parkinson’s (“Translating Science”).  Throughout much of the posts here, I firmly believe that words/concepts like hope, positive, persistent, staying happy and healthy, exercise (a lot, daily if possible), and refuse to give up are all important ‘life-lines’ for us to adopt in our dealing with this disorder.  Today’s message returns to hope and “HOPE”.  Hope is defined by the Cambridge dictionary as “the feeling that something desired can be had or will happen”.  I use HOPE as an acronym in Parkinson’s and it stands for:

H = Hope/Health(y)
O = Optimistic/Positive
P = Persistent/Perseverance
E = Enthusiasm for life, for career, and for exercise

Steve Gleason said “Life is difficult. Not just for me or other ALS patients. Life is difficult for everyone. Finding ways to make life meaningful and purposeful and rewarding, doing the activities that you love and spending time with the people that you love – I think that’s the meaning of this human experience.”  I really like the sentiment of his statement and admire his courage through adversity.  It reminds me that we are a community with a shared theme; while we are spread out throughout the world, we understand one another because Parkinson’s has been sewn in to the fabric of our lives. I am also convinced that staying hopeful and using HOPE gives us tenacity to deal with the subtle changes being forced upon us by the ever present Parkinson’s.

“Your qualifications, your CV, are not your life, though you will meet many people of my age and older who confuse the two. Life is difficult, and complicated, and beyond anyone’s control, and the humility to know that will enable you to survive its vicissitudes.” J.K. Rowling

Living and working with HOPE: This current post reinforces the meaning for HOPE.  It reminds me of Stevie Nicks and Fleetwood Mac’s Landslide where she sings “Can I sail through the changin‘ ocean tides? / Can I handle the seasons of my life?” We confront both of these questions daily with Parkinson’s.  My hope is you find reassurance that your life and world are still meaningful, and you are not battling Parkinson’s alone. We know and we understand what you are confronting each day; thus, be persistent and remain hopeful.

Here is a link to a SlideShare file that will allow you to easily read/view all of these 1-page handouts.  You do not need a login, it’s free. You can read, clip and copy individual slides (1-page handouts); it even will let you download the entire file: click here to view Living and Working with “HOPE” in the Presence of Parkinson’s. Alternatively, here is the URL: https://www.slideshare.net/FrankChurch1/living-and-working-with-hope-in-the-presence-of-parkinsons  And finally, in case the above link proves problematic, here is a copy of these 1-page summaries (click here to download PDF file).  I have enjoyed re-reading the old blog posts these were derived from (some of these were previously posted and several are new) and they are presented as follows:

  • Part 1: Some of Frank’s quotes about living with Parkinson’s (four 1-page handouts);
  • Part 2: Suggestions, character traits, and tips for the journey through life and career in the absence and presence of Parkinson’s (seven 1-page summaries);
  • Part 3: Health and exercise while living with Parkinson’s (five 1-page summaries);
  • Part 4: Historical time-line of Parkinson’s disease (six 1-page reports)

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

Know that wherever you are in your life right now is both temporary, and exactly where you are supposed to be. You have arrived at this moment to learn what you must learn, so you can become the person you need to be to create the life you truly want. Even when life is difficult or challenging-especially when life is difficult and challenging-the present is always an opportunity for us to learn, grow, and become better than we’ve ever been before.” Hal Elrod

Cover photo credit: asisbiz.com/USA/17-Mile-Drive/images/The-Lonely-Cypress-Tree-17-Mile-Drive-Monterey-California-July-2011-06.jpg

A Good Life With Parkinson’s

“I choose to make the rest of my life the best of my life.” Louise Hay

“Avoiding problems you need to face is avoiding the life you need to live.” Paulo Coelho

Try to live following the advice of the opening quotes: Today renews your lease on the rest of your life, enjoy it (get up, get out, get going). Today acknowledge your Parkinson’s; give it a nudge, because you are ready for the battle and for life.

18.01.13b.Live_Better_PD

Live a better and healthier life by following this circle of words [yes, they all begin with the letter ‘F’ (click here to download the schematic above)]:
Fit/fitness-
Exercise as much as your body can take, then do some more. Getting/staying fit really matters in your battle with Parkinson’s.

Fortitude-
Stay strong in your effort with your adversity.

Food- Feed your brain properly, fuel your body well; it will make a difference.

Flexible (two definitions)-
Stay flexible by frequent (I mean really often) stretching; you’ve got a life-altering disorder, stay flexible and let your life follow what happens because it’ll be okay.

Fulltime– It takes time and effort to manage your life. You can find the time because managing your life well from this minute on will matter later in your life;

Faith (multiple definitions)– Believe in your ability to successfully navigate your life; trust in your loved ones to support your journey; believe that a higher entity truly loves you and acknowledges your strength and passion for life.

Forty-winks and sleep some more- The brain is like a sponge that fills up all day with fluid; sleep allows the brain to drain, to renew, to fire-up strong upon waking; sleep is a very good thing.

A Good Life With Parkinson’s: Our Common Bond and Hope
I feel your stiffness; I know it well.

I sense your troubled thoughts; my mind also has questions.
I notice your tremor; mine can act up too.
I perceive your frustation; life with Parkinson’s can be problematic.
I see your shuffle; my right leg drags when I’m tired.
I admire your strength; I’ve got it too.
I acknowledge your life-accomplishments; we are still the same person as before Parkinson’s.
I see your honor; our work our living makes a difference.
I see your smile; those around us still care for us, no matter what.
I feel your effort; like you, I’ll never give up.

“Life is an opportunity, benefit from it. Life is beauty, admire it. Life is a dream, realize it. Life is a challenge, meet it. Life is a duty, complete it. Life is a game, play it. Life is a promise, fulfill it. Life is sorrow, overcome it. Life is a song, sing it. Life is a struggle, accept it. Life is a tragedy, confront it. Life is an adventure, dare it. Life is luck, make it. Life is too precious, do not destroy it. Life is life, fight for it.” Mother Teresa

Cover photo credit: http://ognature.com/path-snow-winter-mist-sunset-sun-trees-wallpaper-iphone-6/

 

Dopamine Agonist Withdrawal Syndrome (DAWS) in Parkinson’s

“Some remedies are worse than the disease.” Publilius Syrus

“Each patient carries his own doctor inside him.” Norman Cousins

Summary: Dopamine agonists are widely used in the treatment of Parkinson’s, especially as a first-line therapy. Some patients on a dopamine agonist experience side-effects that require either tapering or discontinuation of the drug.  First described in 2010, dopamine agonist withdrawal syndrome (DAWS) is a complication of ~20% of Parkinson’s patients who are either lowering or stopping the dopamine agonist.  DAWS presents as a cluster of physical and behavioral symptoms [e.g., agitation, depression, drug craving, and panic attacks (to give a few possible symptoms)]. There is no known standard-of-care in dealing with DAWS in Parkinson’s. Presented here is a brief overview of DAWS in Parkinson’s including dopamine agonists, clinical description, risk factors and prevalence, mechanism of action, treatment/management, and key publications.

“To heal illness, begin by restoring balance.” Caroline Myss

Dopamine agonists (DA): Dopamine agonists are ‘mimics’ of dopamine that pass through the blood brain barrier to interact with target dopamine receptors. Symptomatic treatment of Parkinson’s remains dopamine replacement, including the DA’s.  Dopamine agonists are frequently the first line of choice for therapy for the just diagnosed Parkinson’s patient. Dopamine agonists do help control motor symptoms in Parkinson’s although there can be significant side-effects (see Table below). Also below is a Table describing DA’s. The DA side effects can become intolerable for some people-with-Parkinson’s, and the decision to taper or withdraw the DA is made. Or maybe you’re a candidate for deep-brain stimulation (DBS) surgery and to calibrate the device you’ll be asked to stop your Parkinson’s medication for a short period of time.

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18.01.03.DA+DAWS

“I enjoy convalescence. It is the part that makes the illness worth while.” George Bernard Shaw

First report of dopamine agonist withdrawal syndrome (DAWS): Dopamine agonist withdrawal syndrome (DAWS) was first described in 2010 by Rabinak and Nirenberg on five of their patients with non-motor impulse control behavioral disorders (ICD) caused by the DA; thus, they were tapered. Two patients were further described in this publication. The first patient was a 67-year-old woman with a six year history of Parkinson’s, and she had been taking various drugs including a DA. She had developed a difficult ICD, and they elected to taper the DA; unexpectedly, she then had severe anxiety and dysphoria. They tried an increase in carbidopa/levodopa and they used other therapy for cognitive behavior control; to no benefit to the patient. They changed her back to the original DA dose and she had a rapid and dramatic improvement in all of her symptoms. This patient continues to use the DA and remains with the difficult ICD.

Patient #2 was a 61-year-old woman with a six-year history of Parkinson’s and likewise an ICD prompted by the DA; she began a DA tapering with increased carbidopa/levodopa medication.  During the DA taper, she developed depression and severe anxiety and became agitated; she also had fatigue and insomnia.  As with Patient #1, adding back the DA improved all of her non-motor symptoms. It took several years for her to successfully reduce her DA doseage. The figure below visually highlights some of the key symptoms of DAWS.

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What both cases shared were prominent psychiatric symptoms, poor response to both additional carbidopa/levodopa (to take the place of the DA) and psychiatric medication; however, both had rapid improvement in their ‘new symptoms’ when placed back on the DA. The majority of DAWS symptoms are presented in the the Table below.Document5“The secret of learning to be sick is this: Illness doesn’t make you less of what you were. You are still you.” Tony Snow

Risk-factors and prevalence of DAWS: Since the original study in 2010, there have been several follow-up studies on DAWS. Some of the studies speculated that a large DA dose in the presence of pre-existing ICD are the most important risk factors for DAWS. The ‘number’ talked about frequently is something called the ‘levodopa equivalent daily dose’ (LEDD) of the dopamine agonist, where it has been suggested that >150 mg was linked to an increased risk of DAWS. Use this on-line program to calculate your LEDD (click here).  Here is an LEDD example: someone taking 14 mg ropinirole/day (with the online algorithm), the LEDD would be 280 mg daily.  What? OK, so what did you say?  This means if you wanted to replace the 14 mg/day ropinirole with carbidopa/levodopa you would need about 300 mg per day of levodopa based on this calculation.  I refer you to do the papers cited at the end of the blog post for more details about LEDD. What is interesting is several of the studies have compared the taper versus total withdrawal of the DA; it does not seem to alter the risk of DAWS.  Good news is if you’re not having any detrimental side effects from the DA, just continue on and you’re good to go. The bad news is if you are having some side effects and you want to try and eliminate them by tapering down need to carefully consult with your neurologist and work up a feasible plan.  Please remember I’m a biochemist, not a physician, and I just am interpreting data from publications.

The prevalence of DAWS has been reported to be between 15 and 19% in patients with Parkinson’s; it seems to be consistently about one-in-five.  As mentioned previously, there appears to be no difference in relative risk of DAWS comparing patients that discontinue DA completely or those that reduce the DA by taper. Based on the percentage mentioned above, this says ~4 out of 5 people-with-Parkinson’s can DA taper without any problems.

“It is in moments of illness that we are compelled to recognize that we live not alone but chained to a creature of a different kingdom, whole worlds apart, who has no knowledge of us and by whom it is impossible to make ourselves understood: our body.” Marcel Proust

DA mechanism of action to cause DAWS:  To recap, DAWS occurs in a subset of patients with Parkinson’s that have had difficulties managing the side effects of a DA, and the decision has been made to remove that DA from the patient’s regimen.  The simplest notion is that you would then replace the DA with an increased dose of carbidopa/levodopa (using the LEDD); however, this is Parkinson’s and this is the brain and it’s just not going to be that easy. The diagram below summarizes a very simplistic view of dopamine and DA’s in their interactions with motor and reward pathways.  There is no doubt that in treating Parkinson’s, the replacement of dopamine is crucial for many different physiological functions in the human body. Dopamine agonists and dopamine share similar binding properties to dopamine receptors. They are very important in improving motor symptoms (through the nigrostriatal pathway) but there is also some potential detrimental crossover to the reward center (through the mesocorticolimbic pathway).  It is this minor pathway that is linked to the increased risk of ICD in some patients being treated with a DA. It is not clear, however from the data published so far that there is a difference in this 20% of the patient population in their mesocorticolimbic circuitry system with the DA in comparison to the other 80% of the population.  In summary, what causes DAWS during DA tapering is not well understood.18.01.07.Dopamine_Motor_Reward“Medicine is intention. Those who are proficient at using intention are good doctors.” Sun Simiao

Treatment/management of DAWS during DA taper:  DAWS is a relatively recent phenomena related to DA withdrawal.  Patients with (i) a predisposition to ICD and (ii) a larger dose of DA are apparently at increased risk of developing DAWS. There is no well-delineated treatment plan that the neurologist can follow; best recommendation (from the papers cited below) is the patient should be tapered at a very slow dose reduction over a long period of time, and see what happens. Clearly, it is crucial that the patient and the neurologist carefully evaluate signs of ICD and DAWS at every visit, especially for patients at high risk.

“The treatments themselves do not ‘cure’ the condition, they simply restore the body’s self-healing ability.” Leon Chaitow

 Summary: As someone with Parkinson’s, I’ve done a lot of reading about treatment strategies (what’s good and what’s not so good). For someone my age there would almost always be a recommendation to begin the DA (the so-called sparing one of levodopa until it’s absolutely needed) and then as symptoms progressed, you would switch over and combine the DA with carbodipa/levodopa.  Had I read the opinions of Dr. Ahlskog in the beginning, I might have opted to start with carbidopa/levodopa without the DA (Ahlskog JE. Cheaper, Simpler, and Better: Tips for Treating Seniors With Parkinson Disease. Mayo Clinic Proceedings. 2011;86(12):1211-6. doi: https://doi.org/10.4065/mcp.2011.0443). Biochemically, DAWS is an interesting problem but there needs to be additional studies to delineate the mechanism of action. Finally  DAWS clinically is worrisome and definitely not well-understood; and likely, the scope of DAWS is under-recognized.

Key References:

  1. Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol. 2010;67(1):58-63. doi: 10.1001/archneurol.2009.294. PubMed PMID: 20065130.
  2. Nirenberg MJ. Dopamine agonist withdrawal syndrome and non-motor symptoms after Parkinson’s disease surgery. Brain. 2010;133(11):e155; author reply e6. doi: 10.1093/brain/awq165. PubMed PMID: 20659959.
  3. Cunnington AL, White L, Hood K. Identification of possible risk factors for the development of dopamine agonist withdrawal syndrome in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(9):1051-2. doi: 10.1016/j.parkreldis.2012.05.012. PubMed PMID: 22677468.
  4. Pondal M, Marras C, Miyasaki J, Moro E, Armstrong MJ, Strafella AP, Shah BB, Fox S, Prashanth LK, Phielipp N, Lang AE. Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic. J Neurol Neurosurg Psychiatry. 2013;84(2):130-5. doi: 10.1136/jnnp-2012-302684. PubMed PMID: 22933817.
  5. Edwards MJ. Dopamine agonist withdrawal syndrome (DAWS): perils of flicking the dopamine ‘switch’. J Neurol Neurosurg Psychiatry. 2013;84(2):120. doi: 10.1136/jnnp-2012-303570. PubMed PMID: 22993451.
  6. Nirenberg MJ. Dopamine agonist withdrawal syndrome: implications for patient care. Drugs Aging. 2013;30(8):587-92. doi: 10.1007/s40266-013-0090-z. PubMed PMID: 23686524.1.
  7. Nirenberg MJ. Dopamine agonist withdrawal syndrome: implications for patient care. Drugs Aging. 2013;30(8):587-92. doi: 10.1007/s40266-013-0090-z. PubMed PMID: 23686524.
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“Life always gives us exactly the teacher we need at every moment. This includes every mosquito, every misfortune, every red light, every traffic jam, every obnoxious supervisor (or employee), every illness, every loss, every moment of joy or depression, every addiction, every piece of garbage, every breath. Every moment is the guru.” Joko Beck

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