Tag Archives: Science

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).

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“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/

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

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“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).

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“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.

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“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)

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“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

Cover photo credit: wallpaper/nature/1024×768/Dawn_skies_over_Gulf_of_St._Lawrence_Prince_Edward_Island_Canada_1024x768.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.

18.01.03.DA+DAWS

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.

18.01.04.DAWS_faces

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.
  8. Solla P, Fasano A, Cannas A, Mulas CS, Marrosu MG, Lang AE, Marrosu F. Dopamine agonist withdrawal syndrome (DAWS) symptoms in Parkinson’s disease patients treated with levodopa-carbidopa intestinal gel infusion. Parkinsonism Relat Disord. 2015;21(8):968-71. doi: 10.1016/j.parkreldis.2015.05.018. PubMed PMID: 26071817.
  9. Huynh NT, Sid-Otmane L, Panisset M, Huot P. A Man With Persistent Dopamine Agonist Withdrawal Syndrome After 7 Years Being Off Dopamine Agonists. Can J Neurol Sci. 2016;43(6):859-60. doi: 10.1017/cjn.2015.389. PubMed PMID: 26842385.
  10. Patel S, Garcia X, Mohammad ME, Yu XX, Vlastaris K, O’Donnell K, Sutton K, Fernandez HH. Dopamine agonist withdrawal syndrome (DAWS) in a tertiary Parkinson disease treatment center. J Neurol Sci. 2017;379:308-11. doi: 10.1016/j.jns.2017.06.022. PubMed PMID: 28716269.
  11. Yu XX, Fernandez HH. Dopamine agonist withdrawal syndrome: A comprehensive review. J Neurol Sci. 2017;374:53-5. doi: 10.1016/j.jns.2016.12.070. PubMed PMID: 28104232.
  12. Solla P, Fasano A, Cannas A, Marrosu F. Dopamine agonist withdrawal syndrome in Parkinson’s disease. J Neurol Sci. 2017;382:47-8. doi: 10.1016/j.jns.2017.08.3263. PubMed PMID: 29111017.

“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

Cover photo credit: f.fwallpapers.com/images/sun-peeking-through-snow-covered-trees.jpg

Agitation- img.aws.livestrongcdn.com/ls-article-image-400/cme/cme_public_images/www_livestrong_com/photos.demandstudios.com/49/85/fotolia_4199215_XS.jpg
Depression- http://www.scientificamerican.com/sciam/cache/file/FCD288AE-5C2E-49F2-85858FA255A8034B_source.jpg
Fatigued- www.belmarrahealth.com/wp-content/uploads/2017/03/fatigue-in-the-elderly-300×200.jpg
Panic attack- lifetimewoman.com/wp-content/uploads/2016/09/panica-1.jpg

Complementary and Alternative Medicine (CAM) and Over-the-Counter Therapies in Parkinson’s

With Parkinson’s, exercise is better than taking a bottle of pills. If you don’t do anything you’ll just stagnate.” Brian Lambert

“With Parkinson’s you have two choices: You can let it control you, or you can control it. And I’ve chosen to control it.” US Senator Isakson

Introduction: Having one of the numerous neurodegenerative disorders can be disheartening, difficult and life-threatening/ending; however, Parkinson’s remains in the forefront of treatment schemes and therapeutic options.  We may have a slowly evolving disorder, yet I remain firmly entrenched both in striking back to try-to-slow its progression and in remaining hopeful that new advances are on the horizon to throttle-back its progression.  Recently, several people have asked for an update on my strategy for treating Parkinson’s.  My plan consists of (i) traditional Parkinson’s medication,  (ii) supplemented by a complementary and alternative medicine (CAM) approach, and (iii) fueled by exercise. My philosophy is simple because I truly believe there are steps I can follow to remain as healthy as possible, which include having a positive mindset to support this effort, and to accept the axiom of the harder I try the better I’ll be.

“Life is to be lived even if we are not healthy.” David Blatt

Complementary and Alternative Medicine (CAM):The National Institutes of Health defines CAM as follows: “Complementary and alternative medicine (CAM) is the term for medical products and practices that are not part of standard medical care. ‘Complementary medicine’ refers to treatments that are used with standard treatment. ‘Alternative medicine’ refers to treatments that are used instead of standard treatment.”  Here is a nice overview of CAM (click here). The National Center for CAM (click here for NCCAM) gives five categories to broadly describe CAM (see below, and followed by some representative components for each of the 5 categories):

17.12.31.CAM_Summary

(1) Alternative medical systems include treatment by traditional Chinese medicine, Ayurveda and naturopathic medicine;
(2) Mind-body interventions like mindfulness meditation;
(3) Biologically-based therapies include over-the-counter natural products and herbal therapies;
(4) Manipulative and body-based methods describe chiropractic and massage therapies;
(5) Energy therapies include techniques such as Reiki and therapeutic touch.

“My way of dealing with Parkinson’s is to keep myself busy and ensure my mind is always occupied.” David Riley

CAM and Parkinson’s: Published CAM clinical trial studies have yielded only a sliver of positive response to slowing the progression of Parkinson’s, several were halted due to no change compared to the placebo-control group. Regardless of these ‘failed’ studies, many have embraced a CAM-based approach to managing their disorder, including me. Please remember that I’m not a clinician, and I’m not trying to convince you to adopt my strategy.  I am a biochemist trained in Hematology but I do read and ponder a lot, especially about Parkinson’s.  We know a lot about Parkinson’s and we’re learning a lot about the molecular details to how it promotes the disease.  There is not a cure although we have a growing array of drugs for therapeutic intervention.  Without a  cure, we look at the causes of Parkinson’s (see schematic below), we consider various CAM options, and we go from there (see schematic below). If you venture into adding to your portfolio of therapy, it is imperative you consult with your Neurologist/family medicine physician beforehand.  Your combined new knowledge with their experience can team-up to make an informed decision about your herb, over-the-counter compound use and its potential benefit/risk ratio.

17.12.31.PD_Cause.CAM“I discovered that I was part of a Parkinson’s community with similar experiences and similar questions that I’d been dealing with alone.”Michael J. Fox

A strategy for treating Parkinson’s: The treatment plan I follow uses traditional medical therapy, CAM (several mind-body/manual practices and numerous natural products) and the glue that ties it all together is exercise.  Presented here is an overview of my medical therapy and CAM natural products. I only list the exercises I am using, not describe or defend them.  Due to my own personal preference for the length of a blog post, I will return to them later this year and include an update of the mind-body/manual practices that I’m currently using. 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 supplements.   The schematic below gives a ‘big-picture’ view of my treatment strategy.

18.01.01.Daily_Take. brain.druge.CAM.Exercise

To some, my treatment plan may seem relatively conservative. It has been developed through conversations with my Neurologist and Internist.  This was followed by studying the medical literature on what has worked in Parkinson’s treatment, the list of compounds to consider was defined/refined (actually, my choice of OTC compounds has been trimmed from several years ago).  My CAM drug/vitamin/natural products strategy for treating Parkinson’s goes as follows: a) compounds (reportedly) able to penetrate the blood brain barrier; b) compounds (possibly) able to slow progression of the disorder; c) compounds that either are anti-oxidative or are anti-inflammatory; d) compounds that don’t adversely alter existing dopamine synthesis/activity; e) compounds that support overall body well-being; and f) compounds that support specific brain/nervous system health/nutrition. [Please consult with your physician before taking any type of supplements.] The Table below presents a detailed overview of my strategy for treating Parkinson’s.

18.01.01.DailyTherapy4Note of caution: Most herbs and supplements have not been rigorously studied as safe and effective treatments for PD. The U.S. Food and Drug Administration (FDA) does not strictly regulate herbs and supplements; therefore, there is no guarantee of safety, strength or purity of supplements.

REPLACING DOPAMINE:
On a daily basis, I use a combination of Carbidopa/Levodopa (25 mg/100 mg tablet x 4 daily, every 5 h on an empty stomach if possible, typically 6AM, 11AM, 4PM, 9PM) and a dopamine agonist Requip XL [Ropinirole 6 mg total (3 x 2 mg tablets) x 3 daily, every 6 h, typically 6AM, noon, 6PM).  This treatment strategy and amount combining Carbidopa/Levodopa and Ropinirole has been in place for the past 18 months (NOTE: I stopped using the additional dopamine agonist Neupro transdermal patch Rotigotine). For an overview on Carbidopa/Levodopa, I highly recommend the following 2 papers:
[1.] 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.
[2.] 1. Espay AJ, Lang AE. Common Myths in the Use of Levodopa in Parkinson Disease: When Clinical Trials Misinform Clinical Practice. JAMA Neurol. 2017. doi: 10.1001/jamaneurol.2017.0348. PubMed PMID: 28459962.

ISRADIPINE:
An FDA-approved calcium-channel blocker (CCB) named Isradipine penetrates the blood brain barrier to block calcium channels and potentially preserve dopamine-making cells. Isradipine may slow the progression of Parkinson’s. The primary use of Isradipine is in hypertension; thus, to treat my pre-hypertension I switched from the diuretic Hydrochlorothiazide to the CCB Isradipine.  A CCB is a more potent drug than a diuretic; importantly, my blood pressure is quite normal now and maybe I’m slowing the progression of my Parkinson’s. Please see this blog post for a review of Isradipine (click here). [Please consult with your physician before taking any type of new medication.

ANTIOXIDANTS/VITAMINS/GENERAL HEALTH:
N-Acetyl-Cysteine (NAC; 600 mg x 3 daily) is a precursor to glutathione, a powerful anti-oxidant. In several studies, NAC has been shown to be neuroprotective in Parkinson’s (click here).  I have recently posted an overview of NAC (click here). Furthermore, the ‘Science of Parkinson’s disease’ has presented their usual outstanding quality in a blog post on NAC in PD (click here);
trans-Resveratrol (200 mg daily) is an antioxidant that crosses the blood-brain barrier, which could reduce both free-radical damage and inflammation in Parkinson’s. If you decide to purchase this compound, the biologically-active form is trans-Resveratrol. The ‘Science of Parkinson’s disease’ has an excellent blog post on Resveratrol in PD (click here);
Grape Seed (100 mg polyphenols, daily) is an antioxidant that crosses the blood-brain barrier, which could reduce both free-radical damage and inflammation in Parkinson’s;
Milk Thistle (Silybum Marianum, 300 mg daily) and its active substance Silymarin protects the liver.  Dr. Jay Lombard in his book, The Brain Wellness Plan, recommends people with PD who take anti-Parkinson’s drugs (metabolized through the liver) to add 300 mg of Silymarin (standardized milk thistle extract) to their daily medication regime.
Melatonin (3 mg 1 hr before sleep) Melatonin is a hormone that promotes sustained sleep. Melatonin is also thought to be neuroprotective (click here);
Probiotic Complex with Acidophilus is a source of ‘friendly’ bacteria to contribute to a healthy GI tract.
Vitamin (daily multiple)
A high-potency multivitamin with minerals to meet requirements of essential nutrients, see label for content [I only take 1 serving instead  of the suggested 2 gummies due to my concern about taking a large amount of Vitamin B6 as described in a recent blog (click here)]:
IMG_2059 copyVitamin D3 (5000 IU 3 times/week) is important for building strong bones. Now we also know that vitamin D3 is almost like ‘brain candy’ because it stimulates hundreds of brain genes, some of which are anti-inflammatory and some support nerve health (click here). Supplementation with vitamin D3 (1200 IU/day) for a year slowed the progression of a certain type of Parkinson’s (click here). Furthermore, augmentation with vitamin D3 was recently shown to slow cognitive issues in Parkinson’s (click here).

NO LONGER TAKE Coenzyme Q10 (CoQ10), Creatine and Vitamin E because they did not delay the progression of Parkinson’s or they were harmful.
NO LONGER TAKE a high potency Vitamin B Complex (see label below) due to my concern that a large excess vitamin B6 could be detrimental to Carbidopa/Levodopa (click here for blog post):
Screen Shot 2018-01-02 at 11.39.56 PM
List of several recent PubMed peer-reviewed CAM reviews (includes a more comprehensive overview of all areas of CAM in treating Parkinson’s):
Bega D, Zadikoff C. Complementary & alternative management of Parkinson’s disease: an evidence-based review of eastern influenced practices. J Mov Disord. 2014;7(2):57-66. doi: 10.14802/jmd.14009. PubMed PMID: 25360229; PMCID: PMC4213533.

Bega D, Gonzalez-Latapi P, Zadikoff C, Simuni T. A Review of the Clinical Evidence for Complementary and Alternative Therapies in Parkinson’s Disease. Current Treatment Options in Neurology. 2014;16(10):314. doi: 10.1007/s11940-014-0314-5.

Ghaffari BD, Kluger B. Mechanisms for alternative treatments in Parkinson’s disease: acupuncture, tai chi, and other treatments. Curr Neurol Neurosci Rep. 2014;14(6):451. doi: 10.1007/s11910-014-0451-y. PubMed PMID: 24760476.

Kim HJ, Jeon B, Chung SJ. Professional ethics in complementary and alternative medicines in management of Parkinson’s disease. J Parkinsons Dis. 2016;6(4):675-83. doi: 10.3233/JPD-160890. PubMed PMID: 27589539; PMCID: PMC5088405.

Kim TH, Cho KH, Jung WS, Lee MS. Herbal medicines for Parkinson’s disease: a systematic review of randomized controlled trials. PLoS One. 2012;7(5):e35695. doi: 10.1371/journal.pone.0035695. PubMed PMID: 22615738; PMCID: PMC3352906.

Wang Y, Xie CL, Wang WW, Lu L, Fu DL, Wang XT, Zheng GQ. Epidemiology of complementary and alternative medicine use in patients with Parkinson’s disease. J Clin Neurosci. 2013;20(8):1062-7. doi: 10.1016/j.jocn.2012.10.022. PubMed PMID: 23815871. 

Today we take control over our Parkinson’s:
Please stay focused on dealing with your disorder.
Please learn as much as you can about Parkinson’s.
Please work with your neurologist to devise your own treatment strategy.
Please stretch and exercise on a daily basis, it will make a difference.
Please be involved in your own disorder; it matters that you are proactive for you.
Please stay positive and focused as you deal with this slowly evolving disease.
Please stay hopeful you can mount a challenge to slow the progression.
Please remain persistent; every morning your battle renews and you must be prepared.

 

In the midst of winter, I found there was, within me, an invincible summer.  And that makes me happy. For it says that no matter how hard the world pushes against me, within me, there’s something stronger – something better, pushing right back.” Albert Camus

Cover photo credit: news.nowmedia.co.za/medialibrary/Article/109153/Wine-grape-crop-6-7-down-in-2016-800×400.jpg

 

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.

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