Category Archives: Dopamine

B Vitamins (Folate, B6, B12) Reduce Homocysteine Levels Produced by Carbidopa/Levodopa Therapy

“The excitement of vitamins, nutrition and metabolism permeated the environment.” Paul D. Boyer

“A substance that makes you ill if you don’t eat it.” Albert Szent-Gyorgy

Introduction: Claire McLean, an amazing-PT who is vital to my life managing my Parkinson’s, posted a very interesting article about the generation of homocysteine from the metabolism of levodopa to dopamine in the brain. Here is the article:

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This was all a very new concept to me. And as an ‘old-time’ biochemist by training, it led me down a trail of wonderful biochemical pathways and definitely a story worth retelling  for anyone taking carbidopa/levodopa.  Excessive generation of homocysteine leads to something called hyper-homocysteinuria, which is very detrimental to the cardiovascular system and even the neurological system.  Over time this could lead to a depletion of several B vitamins, which themselves would have biochemical consequences. This post is about the supplementation with a complex of B vitamins (including a cautionary note) during long-term therapy with carbidopa/levodopa.

“There are living systems; there is no ‘living matter’.” Jacques Monod

A reminder about Parkinson’s, dopamine and carbidopa/levodopa:  Someone with Parkinson’s  has reduced  synthesis of dopamine, an essential neurotransmitter produced by the substantia nigra of the midbrain region. A common medical treatment for Parkinson’s is the replacement of dopamine with its immediate precursor levodopa. Here are some of the key aspects regarding use of carbidopa/levodopa for treating Parkinson’s:

  1. Dopamine does not make it through the blood brain barrier to get to the brain;
  2. Levodopa (also known as L-3,4,-dihydroxyphenylalanine) is an amino acid that can cross the blood brain barrier and then be converted to dopamine;
  3. In the G.I. tract and the bloodstream, levodopa can be converted to dopamine by an enzyme named aromatic-L-amino-acid decarboxylase (DOPA decarboxylase or DDC),  which reduces the amount of levodopa that reaches the brain;
  4.  Carbidopa is a small molecule that prevents DOPA decarboxylase from converting levodopa to dopamine;
  5.  Carbidopa cannot pass through the blood brain barrier;
  6.  The “gold standard” treatment for Parkinson’s is a combination of carbidopa/levodopa, these drugs are commonly known as Sinemet, Sinemet CR, and Parcopa;
  7.  To review, we ingest carbidopa/levodopa, the carbidopa inhibits tissue enzymes that would break down the levodopa, this allows the levodopa to reach the blood-brain barrier, and then get converted to dopamine in the brain.
  8. Important side-note: Levodopa is an amino acid that crosses the blood brain barrier through a molecular amino acid transporter that binds amino acids.  Thus, eating and digestion of a protein-rich meal (also to be broken down to amino acids) either before or with your carbidopa/levodopa dose would competitively lower transport of levodopa across the blood brain barrier.  You should have been advised to take your carbidopa/levodopa doses (i) on an empty stomach, (ii) ~1 hr before eating or (iii) ~1-2 hr after eating (assuming you can tolerate it and the drug doesn’t cause nausea); this would insure your dose of levodopa gets across the blood brain barrier.

Here are the structures of the main players (top-left panel is levodopa; top-right panel is carbidopa; and the most commonly used dose is 25/100 immediate release carbidopa-levodopa (tablet with 25 mg carbidopa and 100 mg levodopa) on the bottom panel.

“The quality of your life is dependent upon the quality of the life of your cells. If the bloodstream is filled with waste products, the resulting environment does not promote a strong, vibrant, healthy cell life-nor a biochemistry capable of creating a balanced emotional life for an individual.” Tony Robbins

What’s the big deal about homocyteine (Hcy)?  Homocysteine is a sulfur-containing amino acid formed by demethylation of the essential amino acid methionine. Methionine is first modified to form S-adenosylmethionine (SAM), the direct precursor of Hcy,  This is important because SAM serves as a methyl-group “donor” in almost all biochemical pathways that need methylation (see figure below).  There are pathways that Hcy follows; importantly, the B vitamins of B6, B12 and folic acid are required for proper recycling/processing of Hcy.   An abnormal increase in levels of Hcy says that some disruption of this cycle has occurred.     Elevated Hcy is associated with a wide range of clinical manifestations, mostly affecting the central nervous system. Elevated Hcy has also been associated with an increased risk for atherosclerotic and thrombotic vascular diseases.  The mechanism for how Hcy damages tissues and cells remains under study; however, many favor the notion that excess Hcy increases oxidative stress.  As you might see why from the figure below, Hcy concentrations may increase as a result of deficiency in folate, vitamin B6 or B12. To recap, Hcy is a key biochemical metabolite focused in the essential methyl-donor pathway, whereby successful utilization of Hcy requires a role for complex B vitamins.  By contrast,  there is substantial evidence for a role of elevated Hcy as a disease risk factor for the cardiovascular and central nervous systems.

SAM+HCY


“We need truth to grow in the same way that we need vitamins, affection and love.” Gary Zukav

Sustained use of carbidopa/levodopa can result in elevated levels of homocysteine: As shown below, one of the reactions on levodopa involves methylation to form a compound named 3-O-methyldopa (3-OMD).   The reaction involves the enzyme catechol-O-methyl-transferase (COMT) and requires SAM as the methyl group donor. There is evidence that plasma Hcy levels are higher in carbidopa/levodopa-treated Parkinson’s patients when compared to controls and untreated Parkinson’s patients.  Interpretation of these results suggest the elevated Hcy levels is due to the drug itself and not from Parkinson’s.

Levodopa-3MO

B vitamins (folate, B6, B12) reduce homocysteine produced by carbidopa/levodopa therapy:   Based on the cycle and loops drawn below, they are not strictly one-way in  that theoretically you can drive the reaction in the reverse direction by using an excess amount of folate (NIH fact sheet, click here), vitamin B6 (NIH fact sheet, click here) and vitamin B12 (NIH fact sheet, click here) to reduce levels of Hcy. Folate supplementation was  previously found to reduces Hcy levels when used to treat an older group of people with vascular disease. Using the scheme depicted below as given in the slideshow there are four points I’d like to make:

  1. One might envision the brain is constantly processing a very small amount of levodopa to dopamine throughout the day. By contrast, we take 100’s of         milligram quantities of levodopa several times a day almost as if  we are giving ourselves a bolus of the precursor that reaches the brain. This scheme suggests that L-DOPA + SAM by COMT will produce Hcy; Over time ↑Hcy levels would be generated, leading to hyper-Hcy. Implied by hyper-Hcy is the consumption of B vitamins like folate, B12 and B6; deficiency of these vitamins would contribute to the body being unable to metabolize the excess Hcy.
  2. The folate/vitamin B12 cycle is crucial for DNA synthesis in our body.  This cycle verifies the essential role of folate and vitamin B12 in our diet and demonstrates their function in a key biochemical pathway. This also suggests that making too much Hcy could potentially consume both folate and B12, which would be detrimental to you. By contrast, the cycle also implies that by taking excess  folate and vitamin B12 you might drive the reaction the other direction and reduce the amount of Hcy generated,  and preserve the biochemical integrity of the cycle.
  3.  The processing of HCy is somewhat dependent on vitamin B6.  In the presence of excess Hcy you would consume the vitamin B6 ; however, the cycle also implies in the presence of an excess of vitamin B6 would allow the processing of Hcy further downstream.
  4.  Finally, unrelated to the B vitamins, the addition of N-Acetyl-cysteine (NAC) to the pathway would generate glutathione, which would help consume the excess Hcy  and also generate a very potent antioxidant compound.

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“1914…Dr. Joseph Goldberger had proven that (pellagra) was related to diet, and later showed that it could be prevented by simply eating liver or yeast. But it wasn’t until the 1940’s…that the ‘modern’ medical world fully accepted pellagra as a vitamin B deficiency.” G. Edward Griffin

Beware of taking a huge excess of vitamin B6 in the presence of carbidopa/levodopa, a cautionary tale: I started taking a supplement that had relatively large amounts of complex B vitamins  (specifically the one labeled number two below) had 100% (400 mcg) folate, 1667% (100 mcg) vitamin B12 and 5000% (100 mg) of vitamin B6 (based on daily requirement from our diet).   Over a period of several days I started feeling stiffer, weaker as if  my medicine had stopped treating my Parkinson’s. I especially noticed it one day while playing golf because I had lost significant yardage on my shots, I was breathing heavily, and I was totally out of sync with my golf swing.  Just in general, my entire body was not functioning well.  Timing wise, I was taking the complex B vitamin pill with my early morning carbidopa/levodopa pill on an empty stomach. Something was suddenly (not subtly) wrong with the way I was feeling, and the only new addition to my treatment strategy was this complex B  vitamin pill. There had to be an explanation.

17.08.16.B_Vitamins

I went home and started thinking like a biochemist, started searching the Internet as an academic scientist, and found the answer in the old archives of the literature.  The older literature says taking more than 15 mg of vitamin B6 daily could compromise the effectiveness of carbidopa to protect levodopa from being activated in the tissues. Thus, I may have been compromising at least one or more doses of levodopa daily by taking 100 mg of vitamin B6 daily.  Let me further say I found that the half-life of vitamin B6 was 55 hours; furthermore, assuming 3L of plasma to absorb the vitamin B6, and a daily dose of 100 mg I plotted the vitamin B6 levels in my bloodstream. The calculation is based on a simple, single compartment elimination model assuming 100% absorbance that happens immediately. The equation is: concentration in plasma (µg/ml vitamin B6) = dose/volume * e^(-k*t) :

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And further inspection of the possible reaction properties between vitamin B6, carbidopa and even levodopa suggests that vitamin B6 could be forming a Schiff Base, which would totally compromise the ability of either compound to function biologically (this is illustrated below).   And I should have known this because some of my earliest publications studied the binding site of various proteins and they were identified using vitamin B6 modifying the amino groups of the proteins (we were mapping heparin-binding sites):

Church, F.C., C.W. Pratt, C.M. Noyes, T. Kalayanamit, G.B. Sherrill, R.B. Tobin, and J.B. Meade (1989) Structural and functional properties of human α-thrombin, phosphopyridoxylated-α-thrombin and γT-thrombin: Identification of lysyl residues in α-thrombin that are critical for heparin and fibrin(ogen) interactions.  J. Biol. Chem. 264: 18419-18425.

Peterson, C.B., C.M. Noyes, J.M. Pecon, F.C. Church and M.N. Blackburn (1987)  Identification of a lysyl residue in antithrombin which is essential for heparin binding.  J. Biol. Chem.  262: 8061-8065.

Whinna, H.C., M.A. Blinder, M. Szewczyk, D.M. Tollefsen and F.C. Church (1991) Role of lysine 173 in heparin binding to heparin cofactor II.  J. Biol. Chem.  266: 8129-813

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“…The Chinese in the 9th century AD utilized a book entitled The Thousand Golden Prescriptions, which described how rice polish could be used to cure beri~beri, as well as other nutritional approaches to the prevention and treatment of disease. It was not until twelve centuries later that the cure for beri~beri was discovered in the West, and it acknowledged to be a vitamin B-1 deficiency disease.” Jeffrey Bland

To take or not to take, complex B vitamin supplementation:  I literally have been writing and working on this post since July; it started as a simple story about the use of complex B vitamins to reduce homocysteine levels as a consequence of chronic carbidopa/levodopa use to manage Parkinson’s.   If you eat a good healthy diet you’re getting plenty of B vitamins. Do you need mega-doses of complex B vitamins? My cautionary note described taking very large amounts of vitamin B6 may be compromising both carbidopa and/or levodopa. You should talk with your Neurologist because it’s straightforward to measure folate, vitamin B6 and B12, and homocysteine levels to see if they are in the normal range if you are taking carbidopa/levodopa. The hidden subplot behind the story is the growing awareness and importance of managing homocysteine levels and also knowing the levels of folate, B6 and B12 to help maintain your neurological health.  Bottom line, if you need it, take a multiple vitamin with only 100 to 200% of your daily need of vitamin B6 (what is shown in panel three and four above). And please be careful if you decide to take a larger dose of vitamin B6 (between 10-100 mg/day).

“A risk-free life is far from being a healthy life. To begin with, the very word “risk” implies worry, and people who worry about every bite of food, sip of water, the air they breathe, the gym sessions they have missed, and the minutiae of vitamin doses are not sending positive signals to their cells. A stressful day sends constant negative messaging to the feedback loop and popping a vitamin pill or choosing whole wheat bread instead of white bread does close to zero to change that.” Deepak Chopra

Cover photo credit:

photos.smugmug.com/Kure-Beach-NC/i-QS7T6sW/2/df8e6878/L/kbp3-L.jpg

 

Milestones in Parkinson’s Disease Research and Discovery

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Slide2

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Slide4

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

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

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

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

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

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

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

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

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

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

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

Slide5

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

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

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

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

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

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

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

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

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

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

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

Treatment of Parkinson’s Psychosis with Nuplazid:~50% of the people with Parkinson’s develop psychotic tendencies. Treatment of their psychosis can be relatively difficult. However, a new drug named Nuplazid™ was recently approved by the FDA specifically designed to treat Parkinson’s psychosis.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

17.03.20b.PD_Drugs_Interactions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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200 Years Ago James Parkinson published “An Essay On The Shaking Palsy”

“I have a form of Parkinson’s disease, which I don’t like. My legs don’t move when my brain tells them to. It’s very frustrating.” George H.W. Bush

“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

Summary: Two hundred years ago in 1817, Dr. James Parkinson published “An Essay On The Shaking Palsy”, which was the first medical document to fully describe Parkinson’s disease  (please click here to read a full-length version of Parkinson’s essay). A short synopsis of the essay and his life are included here.

James Parkinson and his essay from 1817

Who was James Parkinson?   I’ve read several review articles about Dr. Parkinson,  and it is clear to me he was a very intelligent, passionate and compassionate person: “James Parkinson (1755–1824) worked as a general practitioner in the semi-urban hamlet of Hoxton, north east of the City of London, where he had been born, and where he lived all his life. The historian Roy Porter considered Parkinson a man ‘with impeccably enlightened credentials,’ a doctor with a highly developed empiricist bent, committed to observation and recording of the human and natural worlds, and faithful to social and political ideals including widening of the franchise and improvements in the material conditions of the majority of people. In addition to his daily work in general practice, James Parkinson was a public health reformer, an advocate of infection control in London workhouses, a medical attendant to a Hoxton madhouse, a writer of political pamphlets and children’s stories, a geologist and fossilist, and the author of a textbook of chemistry.” ( click here to read the full citation)

Review about Dr. Parkinson: (click here to read article), Morris, AD (April 1955). “James Parkinson, born April 11, 1755”. Lancet. 268 (6867): 761–3. PMID 14368866.

Title page to the essay: (click here for a nice historical perspective of Parkinson’s disease). Publication: Parkinson J. 1817. An essay on the shaking palsy. Whittingham and Rowland for Sherwood, Needly and Jones, London. .

Parkinson.paper

The Essay: Much has been written about the essay composed by Dr. Parkinson. Simply stated it is remarkably accurate in its depiction of Parkinson’s disease, which he called shaking palsy.   My goal in this post is not to exhaustively review his essay;  however, after reading this overview I hope you decide to read the essay. (Click here to read a full-length version of Parkinson’s essay).

 Definition of a new disease:  Dr. Parkinson described it as a disease that had an “Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace: the senses and intellects being uninjured.”   We know today that there are both motor and non-motor issues involved with Parkinson’s.

Knowledge that the patients were suffering:  Dr. Parkinson was most aware of what these patients were going through “the unhappy sufferer has considered it as an evil, from the domination of which he had no prospect of escape.”

Detailed and exacting description of the patients:  One of the more  interesting features about the essay is the detailed description of the six patients Dr. Parkinson observed: “So slight and nearly imperceptible are the first inroads of this malady, and so extremely slow its progress, that it rarely happens, that the patient can form any recollection of the precise period of its commencement. The first symptoms are a slight sense of weakness, with a proneness to trembling in some particular part; sometimes in the head, but most commonly in one of the hands and arms.” And here as well, “But as the malady proceeds, even this temporary mitigation of suffering from the agitation of the limbs is denied. The propensity to lean forward becomes invincible, and the patient is thereby forced to step on the toes and fore part of the feet, whilst the upper part of the body is thrown so far forward as to render it difficult to avoid falling on the face. In some cases, when this state of the malady is attained, the patient can no longer exercise himself by walking in his usual manner, but is thrown on the toes and forepart of the feet; being, at the same time, irresistibly impelled to take much quicker and shorter steps, and thereby to adopt unwillingly a running pace. In some cases it is found necessary entirely to substitute running for walking; since otherwise the patient, on proceeding only a very few paces, would inevitably fall.”  Dr. Parkinson also noted there was a sleeping disorder component, “In this stage, the sleep becomes much disturbed. The tremulous motion of the limbs occur during sleep, and augment until they awaken the patient, and frequently with much agitation and alarm.”

Hope for a cure: After describing the six patients in his essay, Dr. Parkinson postulated whether or not there was going to be a cure for this new disease? “On the contrary, there appears to be sufficient reason for hoping that some remedial process may ere long be discovered, by which, at least, the progress of the disease may be stopped. It seldom happens that the agitation extends beyond the arms within the first two years; which period, therefore, if we were disposed to divide the disease into stages, might be said to comprise the first stage. In this period, it is very probable, that remedial means might be employed with success: and even, if unfortunately deferred to a later period, they might then arrest the farther progress of the disease, although the removing of the effects already produced, might be hardly to be expected.”   We’ve come a long way in two hundred years in our understanding of this disease; however, we’ve yet to cure Parkinson’s.

A new disease:  Dr. Parkinson was convinced he had described a new disease. As neurology evolved over the next several decades, others read the essay and agreed. Dr. Jean-Martin Charcot  (the acknowledged father of modern neurology) suggested that Dr. Parkinson’s name be linked to the disease he had so accurately described; thus, “maladie de Parkinson” (Parkinson’s disease).  For an additional summary on Parkinson’s disease, and the man behind the discovery please click here

Closing thoughts about Dr. Parkinson: Clearly, Dr. Parkinson was a most talented individual; he was driven to be a good physician and to be an observant scientist.  With  this attention to detail, he was the first to really accurately describe this disease. And  if that wasn’t enough, Dr. Parkinson had a fossil named after him  because  of his interest in geology and paleontology if you’re interested in additional aspects of his life please click and read this paper. I  encourage you to look through any of the papers cited here; you will gain tremendous respect for Dr. James Parkinson.

 To conclude, here are three quotes about Parkinson’s disease:
“realized while I was announcing myself to the group that I was conceding something profound: that the diagnosis marked an irreversible change in my identity, the moment that one version of me ended and another version” Jon Palfreman (Brain Storms: The Race to Unlock the Mysteries of Parkinson’s Disease)
•The next time you are imagining the worst, look up the definition of imagination.” Robert Lyman Baittie (Tremors in the Universe: A Personal Journey of Discovery with Parkinson’s Disease and Spirituality)
•”Without the quest, there can be no epiphany.” Constantine E. Scaros (Reflections on a Simple Twist of Fate: Literature, Art and Parkinson’s Disease)

 

Cover photo credit: https://s-media-cache-ak0.pinimg.com/originals/55/3d/2c/553d2ccd51dd6610cfa91939c4905b96.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.

17-02-06-jan-jun-2016

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

17-02-06-jul-dec-2016

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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The Mask of Parkinson’s

“I wear the mask. It does not wear me.” Man in the Iron Mask

“See to it, then, that the light within you is not darkness.” Luke 11:35

Précis: The simplest way to describe Parkinson’s is that it’s a movement disorder due to the reduction of dopamine production.  Sometimes one of the more obvious places this absence of dopamine is noticed is the reduction of facial expressions (also referred to as masked facies or hypomimia).  The “mask of Parkinson’s” is further described below.

Loss of facial expression: There are 43 muscles in the face, which are all mostly controlled by the seventh cranial nerve.  Johann Kaspar Lavater said “…The human face is nature’s tablet, the truth is certainly written thereon.” We view the smile as a sign of friendship, happiness, and acceptance; while we view the frown as a sign of sadness or unacceptable.  The Parkinson’s face is somewhat less expressive than before; somewhat more rigid than before.  Many people-with-Parkinson’s also have chronic stiff necks; however, that doesn’t make us Frankenstein.

Scenario #1: You’ve played 17 holes of golf, and you approach the 18th hole to finish the round. This is a long par three with a lake between you on the tee box and the putting surface.  Your three golf buddies have already safely hit their balls over the lake;  you  launch the ball over the water and safely onto the green (this is a big deal).  Without Parkinson’s, your facial expression and your exuberance are so obvious.  With Parkinson’s, your joy and exuberance are still over-flowing inwardly yet it is displayed in a more muted  manner.

‘Life is a mask through which the universe expresses itself.” Frank Herbert

“You wear a mask for so long, you forget who you were beneath it.” Alan Moore

Changes in your voice: The loss of dopamine in your brain leads to reduced volume in your voice along with your voice becoming flatter/softer in tone.  The same process affecting your face is happening in your voice. If you think of dopamine as a “messenger service”, the brain uses it to send orders/messages to nerves.  When dopamine-producing cells die, all muscles are affected and diminish, including muscles involved in speaking, swallowing, facial motion, legs and  walking, and hand/arm movements.

Scenario #2:  You and your partner are attending a college basketball game;  your home team is 3-points ahead of your biggest rival, and it’s near the end of the second half.  Game over, your team wins, let the fun begin.  Like everyone else in the arena, you are standing, jumping around, high-five’s all near you, and you are shouting (and singing) your lungs out.  Such happens during great college basketball rivalry games.  Without Parkinson’s, all of this is a reality, a dream come true.  There is a feeling of satisfaction and there is a huge positive feeling from the game.  With Parkinson’s, there is the same positive feeling of happiness but with a diminished ability to clap  continuously and you’re less able to shout and sing along loudly with everybody.

Two famous masks:

“Without wearing any mask we are conscious of, we have a special face for each friend.’ Oliver Wendell Holmes

“A mask tells us more than a face.” Oscar Wilde

Consequences of the ‘Parkinson’s Mask’: The change is subtle over time. Mostly,  there is a softness to your voice, your smile is not as big, and you don’t blink your eyes as much.

Subtle differences in the before/after pictures (I’m also younger in the without PD pictures):

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Because I do a lot of teaching, I get a lot of teaching evaluations and critiques. Here are two comments from two medical students regarding my lecturing in Immunology (one of the medical school courses I co-direct and teach in):

“Dr. Church is a wonderful lecturer! Not only is he easy to follow during lectures as far as explaining concepts is concerned, but his dedication to his students, their questions, and their general well-being never ceases to amaze me.

“Dr. Church should take it as a huge compliment that he was able to convey enthusiasm about the topic and inspire passion in students despite his expression often being limited by Parkinson’s.”

LSVT LOUD® can certainly help boost the volume and tone of your voice. If you use it and practice, it will make a difference.  My Speech Pathologists told me that we think we’re speaking at a normal volume but we’re really not.  Your goal is to train your brain to really speak loud (almost shouting). You can also practice making accentuated facial motions, trying to accentuate what’s going on with your face. You can practice smiling large, and other facial exercises (try practicing your vowels).  I have never had a loud voice and I’m not an overly expressive person; having Parkinson’s has softened everything. When you listen to someone speaking, you also listen with your eyes; thus,  the reduction in visual cues makes it harder to understand you.  To continue to get these positive comments shown above, I need to be constantly practicing on speaking louder and working on my facial exercises.

“Take the emotional temperature of those listening to you. Facial expressions, voice inflection and posture give clues to a person’s mood and attitude.” John C. Maxwell

“People are like stained – glass windows. They sparkle and shine when the sun is out, but when the darkness sets in, their true beauty is revealed only if there is a light from within.” Elisabeth Kubler-Ross

Resist the evolving Parkinson’s mask:  The worst-case scenario to what I’ve been describing is the total outward masking/blocking of your inner self and its expression. We must resist that change, we must really work hard to speak louder and to over-accentuate our facial motion to show the emotion that’s within us. Change may be subtle but change is inevitable for most of us regarding this mask. Stay vigilant. Let’s keep working on talking louder and being more expressive. The inner you is still there, it’s functioning and still wanting to get out. Keep working.

“When we can let go of what other people think and own our story, we gain access to our worthiness—the feeling that we are enough just as we are and that we are worthy of love and belonging. When we spend a lifetime trying to distance ourselves from the parts of our lives that don’t fit with who we think we’re supposed to be, we stand outside of our story and hustle for our worthiness by constantly performing, perfecting, pleasing, and proving. Our sense of worthiness—that critically important piece that gives us access to love and belonging—lives inside of our story.” Brené Brown

Cover photo credit: http://7-themes.com/6793576-free-pacific-ocean-wallpaper.html

The 23andMe Parkinson’s Research Study

“Somewhere, something incredible is waiting to be known.” Carl Sagan

“A dream doesn’t become reality through magic; it takes sweat, determination and hard work.” Colin Powell

Introduction/Background: Parkinson’s disease is a neurodegenerative disorder that affects movement. It evolves slowly, usually starting as either stiffness in a hand or a small tremor. Over time, Parkinson’s progresses; typically characterized by motor symptoms such as slowness of movement (bradykinesia) with rigidity, resting tremor (Parkinsonian tremor), balance and walking problems, and difficulty swallowing and talking. Parkinson’s has several non-motor symptoms including anxiety, depression, insomnia  and psychosis (just to mention a few). ~60,000 new cases of Parkinson’s disease are diagnosed each year in the United States, adding to the greater than one million people who currently have Parkinson’s.  It has been estimated that 7-10 million people worldwide are living with Parkinson’s.

“Enclose your heart in times of need with the steel of your determination and your strength. In doing this, all things will be bearable.” Lora Leigh

Genetic Testing and Introduction/Background to 23andMe:
What is the “Central Dogma of Life”? (click here) The process of how the information and instructions found in DNA to become a functional protein is termed the ‘Central Dogma’.  The concept of the central dogma was first proposed in 1958 by Francis Crick, one of the discoverers of the structure of DNA. The central dogma states that the pattern of information that occurs most frequently in our cells is as follows: (i) use existing DNA to make new DNA  (replication); (ii) next, from DNA to make new RNA (transcription); and (iii) finally, using RNA to synthesize new protein (translation). The drawing below depicts the central dogma (the drawing is from this video, click here).


23andMe: What does the name 23andMe represent? Our genetic material  (genes) are housed in chromosomes and they are composed of DNA. We have 23 pairs of chromosomes in each cell capable of producing new proteins; thus, the name of the company makes sense.  23andMe provides DNA testing services.  The information derived from studying your DNA and genetic make-up can provide information about your ancestry, your genetic predisposition to many different diseases, drug responses and inherited conditions.

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“When burned on a CD, the human genome is smaller than Microsoft Office.” Steve Jurvetson

There’s an old saying that goes “Mother is always right.”:  My mother said for her entire life that we were English, Scottish (or Irish), French and German in our ancestral ‘gene pool’.  Several years ago, my extended family and I took to spitting into the 23andMe test-tubes.  We mailed them back to the company to establish our genetic history and screen our family gene pool for several diseases and their inherited susceptibility. Guess what?  Mom was absolutely right about our family ancestry.  Interestingly, there was no evidence of early onset Parkinson’s in my extended family; thus, my disorder is the sporadic/idiopathic type of Parkinson’s.

“A mother’s love for her child is like nothing else in the world. It knows no law, no pity, it dares all things and crushes down remorselessly all that stands in its path.” Agatha Christie

The 23andMe Parkinson’s research study: A few years ago, 23andMe decided to better understand the genetics of Parkinson’s disease; thus, the Parkinson’s research initiative.  Their goal is as follows: to understand the genetic associations found between Parkinson’s patients’ DNA and our disease; to take this new knowledge and search for a cure; and ultimately, they strive to enhance and speed-up how Parkinson’s disease is studied to better understand the genetics of the disease (click here to read further details) It’s easy to get involved in the 23andMe Parkinson’s research study, here are the eligibility requirements: (1) You have been diagnosed with Parkinson’s disease by a qualified physician; (2) You are willing to submit a saliva sample for DNA testing and complete online surveys related to your condition; (3) You have access to the internet; and (4) You are at least 18 years old.  The flow-chart below shows all one has to do to join this community of people-with-Parkinson’s helping out to search for a cure.
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23andMe has an impressive group of  primary research partners and several other organizations as supporting partners, see below. To date, more than 10,000 people have agreed to be in 23andMe’s Parkinson’s Research Community, which makes it the world’s largest collective of genotyped Parkinson’s patients. Furthermore, many thousands of people without Parkinson’s have also consented to participate in these research studies.

16.07.21.2 “Research is to see what everybody else has seen, and to think what nobody else has thought.” Albert Szent-Gyorgyi

It’s a personal decision and choice, but it’s also advancing our knowledge of Parkinson’s:  If you have concerns, look over the 3 websites cited below.  The question is should you volunteer your DNA for the study?  Should you consent to have your DNA further sequenced?  And the nice thing about being involved is you don’t have to leave your home to participate; it’s an in-house study in that they mail you the tube/device, you spit into it, and mail it back to 23andMe.  Simple. Valuable. Straightforward. Elegant.  Contributing. Joining the Parkinson’s team.

7 Things You Should Know About The Future Of Your Genetic Data (click here)
23andMe DNA Test Review: It’s Right For Me But Is It Right for You? (click here)
DNATestingChoice.com (click here for a review of 23andMe)

Ponder it, think about it some more, possibly fill out the questionnaire, upload the information, you are now part of the Parkinson’s 23andMe team. Why should you participate? You will be providing your own small piece to the Parkinson’s genetic puzzle; help complete the assembly of the landscape to this amazing puzzle.

You will matter whether you participate or not; you will always matter.  However, congratulate yourself if you decide to join the team; the 23andMe Parkinson’s research study.  You can be part of the unraveling and the delineation of the genetic anomalies that cause Parkinson’s.

“It is ironic that in the same year we celebrate the 50th anniversary of the discovery of DNA, some would have us ban certain forms of DNA medical research. Restricting medical research has very real human consequences, measured in loss of life and tremendous suffering for patients and their families.” Michael J. Fox

Cover photo credit: http://www.hdwallpapersact.com/wp-content/uploads/2013/04/ summer-sunset-on-beach-hd.jpg

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