Category Archives: Neuroscience

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.

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  • 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

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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.

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“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

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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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“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.
  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

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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
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Panic attack- lifetimewoman.com/wp-content/uploads/2016/09/panica-1.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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cover photo image: https://img1.10bestmedia.com/Images/Photos/304499/Pier-orange-sky-compressed_54_990x660.jpg

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

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2016: The Year in Parkinson’s

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

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

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

Part 1. A personal Parkinson’s 2016 calendar review

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Part 1: Journey to Parkinson’s and Barium Swallow

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

 

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