Category Archives: Life Expectancy

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.

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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

 

Part 1 of 2017 PWR! (Parkinson Wellness Recovery) Retreat: Pictures With Great Memories

“Just put one foot in front of the other.”  Austin Peck

“Coming together is a beginning; keeping together is progress; working together is success.”  Henry Ford

Introduction to Part 1: From May 28-June 3, >100 people came to Scottsdale, Arizona for the PWR! Retreat. The final tally had >50 people-with-Parkinson’s, more than 30 care partners and ~20 physical therapists/fitness professionals, and PWR! Gym staff.

Simply stated,  participating in my first PWR! Retreat was life-altering, life-changing and possibly even life-saving. It will be hard to put into words what the week meant to me and  what it did for me.

I have decided to write 2 posts describing the PWR! Retreat,  Part 1 contains: (i) overview of week; (ii) instructors; (iii) impressions of format, instructors, teams, and location; and (iv) video presentation describing the entire week.

“Alone we can do so little; together we can do so much.”  Helen Keller

Video presentation describing the entire week:   I want to begin with the finale and show a video compiled to highlight the week of the PWR! Retreat. The vast majority of pictures shown in the video were either taken by or obtained from Claire McLean. A few things I want to highlight about the PWR! Retreat that you will see in the video include the following: a) it was a tremendous amount of fun; b) it was a lot of work physically because we exercised several hours every day; c) there was total camaraderie and synergy throughout the week; d)  every afternoon was spent being educated about Parkinson’s; e)  the physical therapists/fitness professionals that led our sessions were all outstanding people and really knew how to work well with everyone with Parkinson’s, and f)  the week revolved around the exercise program and philosophy created by Dr. Becky Farley  (Founder and CEO of Parkinson Wellness Recovery), and in reality, she was the reason we were all at the PWR! Retreat.

Assembling the pictures and putting it all together into the video format left me somewhat speechless. The video brought back so many wonderful memories of the interactions with everybody and it reminded me of the intensity of the exercise.  Watching the video allowed me to recall the sheer quality and quantity of the education  program presented, and it let me reminiscence about the sincerity and friendliness of everyone present.   It just felt like everyone wanted to be at the PWR! Retreat every single second of that week.

Video of 2017 PWR! Retreat: Pictures With Great Memories (to access the YouTube site, please click here).

“We keep moving forward, opening new doors, and doing new things, because we’re curious and curiosity keeps leading us down new paths.” Walt Disney

PWR! Retreat agenda and overview of the week (Click here to view Program ): There were basically two-sessions per day.  The morning always began for everyone with a PWR-Walk with poles at 6:30 AM, then breakfast and then separate programs for those of us with Parkinson’s (exercise) and Care Partners (a mixture of education sessions, group discussions and/or exercise), and sometimes we were combined together (which was always fun). Lunch was next.  The afternoon session was usually all-inclusive of participants and we listened to experts discuss many aspects of Parkinson’s, we had group discussions, and we had sessions of yoga, meditation, Tai Chi and other modalities (e.g., deep-brain stimulation surgery or DBS) used to treat Parkinson’s. The day usually ended at 5:30 PM and dinner was on our own.  Many came back after dinner to the game room, we had a dance night, I played golf on 4 different evenings, many of us returned to the resort bar/club to socialize and many people checked in early because an 11-hour day was incredibly fun but also it was tiring. All-in-all, the agenda was completell, well-rounded, and most enjoyable.  We were never bored.

“I find that the best way to do things is to constantly move forward and to never doubt anything and keep moving forward, if you make a mistake say you made a mistake.”  John Frusciante

PWR! Retreat instructors (brief biographies of the people who led our instructions; presented in alphabetical order after Dr. Farley):  To me, exercise  was the most important aspect of the retreat, followed by meeting everyone with Parkinson’s, and then equally important, the educational program.   Therefore, I want to present the physical therapists/fitness professionals, volunteers and staff that provided us our workout each day.  Each person was uniquely qualified; in my opinion, together as a team they have no equal. Here are a few comments about each one of the instructors.

•Dr. Becky Farley has a PhD in neuroscience from the University of Arizona, a Masters of science physical therapy from the University of North Carolina at Chapel Hill, and a bachelor of physical therapy from the University of Oklahoma.  During her post-doctorate, she developed the LSVT Big therapy program. Following this, she created the exercise program of PWR!Moves, opened the PWR! Gym that follows a philosophy centered on exercise is medicine and framework call PWR!4Life; in all this is contained within the nonprofit organization called Parkinson Wellness Recovery (PWR!).  The PWR! Retreat begins and ends with Dr. Farley; she’s clearly the heartbeat of why we were in Arizona.

•Dr. Jennifer Bazan-Wigle has her doctorate of physical therapy from Nova Southeastern University. She is an expert in treating individuals with Parkinson’s and various movement disorders and works at the PWR!Gym in Tucson, Arizona.  My history with Jennifer starts in 2016 when she was my instructor for PWR!Moves certification;  she was a motivated teacher, very knowledgeable about Parkinson’s and had intensity and the drive to really focus us to learn the material.  Jennifer is a role model for a physical therapist, and she is an amazing educator for working with those of us with Parkinson’s.

Jan Beyer completed her Masters in health education from Cortland state New York and started her own personal training business called “FitJan”.   She now lives and works in the Vancouver, Washington area where she’s working for the Quarry Senior living as the fitness director/Parkinson’s director.

Dr. Emily Borchers has her doctorate in physical therapy from Ohio State University and she currently works at the PWR!Gym.  Emily was very effective at sharing her expertise in helping teach all of the individuals with Parkinson’s.

Heleen Burghout has a Masters degree in physiotherapy from University of Amsterdam,  the Netherlands; and she has a primary care practice called ‘FhysioAlign’ in Ede,  the Netherlands. One of the main focuses of her practice is dealing with exercise and improving physical and mental conditions of people with Parkinson’s.

Dr. Valerie A. Carter has a doctorate in physical therapy from Northern Arizona University in Flagstaff Arizona and is an associate clinical professor of physical therapy at Northern Arizona University.  She is certified and has taught workshops in both PWR! Moves and LSVT Big.  She owns and operates “Carter rehabilitation and wellness center and outpatient physical therapy clinic” in Flagstaff and she is an expert dealing with Parkinson’s patients.

Dr. Carl DeLuca has a doctorate in physical therapy from the University of Wisconsin-Madison.  He works in Wisconsin Rapids Wisconsin and is focused on a patient population with outpatient orthopedic and neurological including people with Parkinson’s.  He is working to set up a central Wisconsin PT program for Parkinson’s.

Dr. Chelsea Duncan has a doctorate in physical therapy from University Southern California and works as an outpatient neurologic clinic that specializes in movement disorders. She focuses in teaching both one-on-one and group exercise classes  for people with Parkinson’s. And she does live in sunny Los Angeles California.

Marge Kinder has a degree in physical therapy from University of California, San Francisco and for more than 40 years has been practicing and treating neurological disorders.  She is the project coordinator for the Redmond Regional Medical Center in Rome Georgia.

Dr. Claire McLean  has a doctorate in physical therapy  from the University of Southern California and is an adjunct faculty member at both University of Southern California and California State University, Long Beach.  She has extensive training and is a board-certified neurologic clinical specialist and teaches both PWR! therapist and instructor courses. She has started a community wellness program for people with Parkinson’s and this is located in Southern California. My experience with Claire is that she was the voice and instructor for the videos that I use in my own training and for my undergraduate class in highlighting PWR! Moves.  Claire is an incredible PT/educator of exercise-and-life-programs for those of us with Parkinson’s.

Nancy Nelson is an ACE certified personal trainer and fitness specialist with over three decades of work experience in the health and wellness industry. She is an expert in dealing with exercise and Parkinson’s.

Sarah Krumme Palmer  has an MS degree in exercise physiology and have been working with patients with Parkinson’s for over 20 years. She is the owner of ‘forever fitness’ in Cincinnati Ohio. She is certified in PWR! moves professional, and has the Rock Steady Boxing affiliate in Cincinnati and has a Certified Strength and Conditioning Specialist (CSCS) certification through the National Strength and Conditioning Association (NSCA).

Kimberly Peute has an MBA from Webster University and is currently a JD candidate University of Arizona School of Law. She was an active participant in the PWR! retreat and was in charge of the care partner program.

•Lisa Robert has a physical therapy degree from the University of Alberta and Edmonton Alberta Canada and has been working in various settings including acute care, private practice and outpatient setting treating neurological patients.   Lisa has NDT, LSVT Big and PWR! Moves professional training experience, and she is a Master Trainer for urban poling. Lisa is also an excellent golfer; I had the opportunity and pleasure to play golf with her twice during the week of the PWR! Retreat.

•Ben Rossi has nearly 20 years of experience in fitness coaching, eight years dealing with the peak Parkinson’s community and as the founder of InMotion, he owns and operates ATP evolution performance training center.  Ben’s goal is straightforward in that he wants you in motion, helps you achieve a better eating program, encourages a positive attitude and he wants you to become 1% better every day.  He lives in Warrensville Heights Ohio.

Melinda Theobald has her MS degree in human movement from the A.T. Still University, Arizona School of Health Sciences, where she is certified by the National Academy sports medicine as corrective exercise specialist and a performance enhancement  specialist.  She currently works for Banner Neuro Wellness West in Sun City Arizona.

•Christy Tolman  has been a licensed realtor for over a decade and  served on the Parkinson’s network of Arizona at the Mohammad Ali Parkinson Center in Phoenix.  She was everything to the PWR! Retreat in terms of organizational skills;  in other words,  the PWR! Retreat was successful because of Christy’s effort.

“If everyone is moving forward together, then success takes care of itself.”  Henry Ford

Impressions of format, instructors, teams, and location: 
Location– Scottsdale Resort in McCormick Ranch in Scottsdale Arizona was the ideal setting for the PWR! Retreat. The resort itself was well-kept and the rooms we used for the retreat were just right; the staff were helpful; it was adjacent to a golf course (great for me); many restaurants/shopping were only minutes away; and the food was just never-ending and really good quality.   I realize you can’t control the weather, but it was ideal sunny, hot and dry with clear skies.
Format–  the format was described above and it seemed ideal for the participants dealing with exercise in the morning and education in the afternoon with evenings free either to do things with your partner or with the group-at-large.
Instructors– They totally rocked!  I cannot imagine a better group of people to teach PWR! Moves and the other exercise (PWR-pole-walking, Circuit and Nexus) routines associated with the PWR! Retreat.  It was also so nice to see them outside of exercise; some gave talks in the afternoon sessions, we had meals together with them , and they were also active participants in all of our other events. 
Teams–   we had four different teams, my team was the Blue team  (For pole walking it was both the people with Parkinson’s and the care partners together, and for the exercise it was typically just the people with Parkinson’s together) and my group did the following sessions together as illustrated by the blue boxes in the table below.   I will describe the experience in more detail in my next post.  However, this was the vital experience that made the PWR! Retreat so valuable, spending time with these people the majority of whom had Parkinson’s (it was a special treat and honor to have the care partners with us for so much time as well because they were remarkable people themselves).

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“Don’t dwell on what went wrong. / Instead, focus on what to do next. / Spend your energies on moving forward / toward finding the answer.” Denis Waitley

Pictures With Great Memories:  Below are posted many of the pictures that were contained in the video I showed in the beginning of the post. My second post I will spend more time talking about the exercise routines, education program, team camaraderie, and my personal feelings behind the week of exercise and everything else associated with the PWR! Retreat.   It’s very safe to say as I remarked at the beginning, the impact of  the PWR! Retreat on me was life altering and very meaningful in a profound manner.

My Team/Program Leaders (names of those missing from pictures are given in the video):

 The Team Leaders and Teams:

Exercise Routines (Pole walking, PWR! Moves, Nexus and Circuit):

 

Dance night, game night and meditation:

 

My Keynote presentation and additional ‘stuff’:

 

 

Additional photos of the PWR! Retreat instructors/organizers:
Screen Shot 2017-07-14 at 9.39.41 AMIMG_5228 (1)Golf fun:

 

Giving thanks and saying good-bye to all of the instructors:

 

 

“I do believe my life has no limits! I want you to feel the same way about your life, no matter what your challenges may be. As we begin our journey together, please take a moment to think about any limitations you’ve placed on your life or that you’ve allowed others to place on it. Now think about what it would be like to be free of those limitations. What would your life be if anything were possible?” Nick Vujicic

Cover photo credit:

http://www.genehanson.com/images/photography/777sunset/020_arizona_sunetset_image0001.jpg

 

 

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Gender Differences as a Factor in Parkinson’s

“Men are from Earth, women are from Earth. Deal with it.” George Carlin

“You can either be a victim of the world or an adventurer in search of treasure. It all depends on how you view your life.” Paulo Coelho

Précis: ~10% of Parkinson’s cases are linked to familial genetic mutations; whereas the vast majority of cases have an unknown cause and are labeled sporadic.  Epidemiological studies have recently shown that the male sex is an adverse factor for developing the sporadic form of Parkinson’s. Presented here is a brief overview that suggests female gonadal substances offer resilience to the loss of dopamine in Parkinson’s.

The nigrostriatal dopaminergic neural pathway:  Parkinson’s begins when dopamine-producing neurons die in the substantia nigra region in the mid-brain. There are four dopamine-dependent neural pathways that originate from the substantia nigra/ventral tegmental area (VTA); most likely, the nigrostriatal dopaminergic pathway has an important role in Parkinson’s (the figure below highlights the brain and dopaminergic pathways; modified from https://upload.wikimedia.org/wikipedia/commons/5/52/Nigrostriatal_pathway.svg).  The nigrostriatal dopaminergic pathway is the connection between the substantia nigra and the striatum (the caudate nucleus and putamen).  This pathway has an important function in supporting and regulating fine motor control (i.e., movement).

Loss of dopamine in the substantia nigra is somewhat analogous to a car engine running without oil; loss of oil (dopamine) eventually leads to engine seizure (stiffness, loss of fine movement control). Loss of dopamine-generating neurons in the substantia nigra is one of the main pathological features of Parkinson’s. The symptoms of the disorder typically do not evolve until a majority of dopamine production has been lost.

Although the loss of dopamine-producing neurons may seem to be a relatively simple process; in reality, Parkinson’s is a complex disorder. As described in detail over the past decade in the scientific literature (and described in various postings in this blog), Parkinson’s cause (etiology) is likely due to complex interactions between numerous genetic factors, changes in the cellular micro-environment, detrimental effects of inflammation, innate and possibly adaptive immune systems, and advanced aging (In a future blog, I will more fully describe the impact of advanced aging and how it contributes to the development of Parkinson’s).  After aging, epidemiological studies have shown that being male is an additional risk factor for developing Parkinson’s (see below).

Nigrostriatal.pathway“It would be possible to describe everything scientifically, but it would make no sense; it would be without meaning, as if you described a Beethoven symphony as a variation of wave pressure.” Albert Einstein

Parkinson’s and being male as a risk factor: Here’s a brief summary of many different studies regarding gender discrepancies in Parkinson’s.
•Parkinson’s appears to have both a greater prevalence and a younger age of onset in men than in women.
•Public health studies indicate that male gender is a bigger risk factor for developing Parkinson’s than female gender at most ages.
•Van Den Eeden et al. (2003) was an early study that noted gender differences; they showed that the incidence of Parkinson’s in men after 60 years of age was greater by 90% then in women.
•As with most public health studies using diverse groups of people, varied by gender, age, race/ethnicity and country of residence, the trends/results described above were similar in many but not in all studies.
Collectively, these studies show that men have both a higher prevalence and a younger age of onset of Parkinson’s than in women.

“Parkinson’s is my toughest fight. No, it doesn’t hurt. It’s hard to explain. I’m being tested to see if I’ll keep praying, to see if I’ll keep my faith.” Muhammad Ali

Men and women with Parkinson’s have different clinical profiles: Summarized below are some of the different clinical features found in women compared to men with Parkinson’s.
•Age of onset in women is later by ~2 years.
•Women typically present with a milder phenotype (observed traits) with a slower disorder progression and less motor decline.
•Women present more often with a tremor.
•Women have more nervousness, sadness, depression and constipation; in contrast, men experience more daytime sleepiness, dribbling and sex-related symptoms.
•Women, compared to men, show differences in Parkinson’s drugs efficacy and pharmacokinetics (what the body does to a drug).
Collectively, these clinical studies suggest that sex influences the nigrostriatal dopaminergic pathway to alter the degenerative processes that promote development of Parkinson’s.  These results imply that the female sex hormone estrogen likely serves a key role in this protective process.

gender4““A woman needs a man like a fish needs a bicycle.” I really hate this expression. I bet fish would totally want bicycles.”  Meg Cabot

The neuroprotective effect of estrogen: There have been many clinical studies on sex differences affecting the brain and linked to Parkinson’s susceptibility; here are some highlights.
•17β-estradiol (E2) is the most abundant estrogen in non-pregnant mammals; E2 is known to have a neuroprotective function.
•E2 may explain why women generally fare better with the neurodegenerative aspects of Parkinson’s.
•Women who had their ovaries (the source of E2) surgically removed (oophorectomy) before menopause have an increased risk of developing Parkinson’s.
•Parkinson’s symptom severity may increase in women at menses when estrogen levels are lowest,
•Estrogen-based hormone replacement therapy (HRT) (a) relieves symptoms in the early stages of Parkinson’s, (b) decrease the risk of developing Parkinson’s, and (c) on cessation of HRT Parkinson’s symptoms may worsen.
•Interestingly, sex differences in Parkinson’s remain following menopause, which suggests that it is more complex than just E2 providing neuroprotection.
These results imply a neuroprotective role for E2 during normal function of the nigrostriatal dopaminergic pathway; furthermore, E2 somehow enables a female to delay developing Parkinson’s. By contrast, male gonadal substances offer little protection to dopamine loss.

“The truth is you don’t know what is going to happen tomorrow. Life is a crazy ride, and nothing is guaranteed.”  Eminem

Concluding thoughts:  Sex matters.  Your sex affects and influences the biology and incidence of many disorders, including Parkinson’s. Women are seemingly protected from both progression and severity of Parkinson’s compared to men.  However, it is important to continue to delineate the molecular details to these sex differences in Parkinson’s. Scientists in this field are hopeful that hormone-specific therapies could be developed to treat and possibly delay the progression of Parkinson’s.
Sex matters.  Yes, sex matters and it is a factor to influence Parkinson’s. You still matter. Male or female. Stay hopeful, positive, persistent, mindful, educated, and keep going, keep going strong. You still matter.

“If you want to identify me, ask me not where I live, or what I like to eat, or how I comb my hair, but ask me what I am living for, in detail, ask me what I think is keeping me from living fully for the thing I want to live for.” Thomas Merton

References:
Van Den Eeden, SK, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity Am. J. Epidemiol., 157 (2003), pp. 1015–1022

Miller IN, Cronin-Golomb A. GENDER DIFFERENCES IN PARKINSON’S DISEASE: CLINICAL CHARACTERISTICS AND COGNITION. Movement disorders: official journal of the Movement Disorder Society. 2010;25(16):2695-2703. doi:10.1002/mds.23388.

Haaxma CA, Bloem BR, Borm GF, et al. Gender differences in Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psychiatry. 2007;78(8):819-824. doi:10.1136/jnnp.2006.103788.

Gillies GE, Pienaar IS, Vohra S, Qamhawi Z. Sex differences in Parkinson’s disease. Frontiers in Neuroendocrinology. 2014;35(3):370-384. doi:10.1016/j.yfrne.2014.02.002.

Mhyre TR, Boyd JT, Hamill RW, Maguire-Zeiss KA. Parkinson’s Disease. Sub-cellular biochemistry. 2012;65:389-455. doi:10.1007/978-94-007-5416-4_16.

Ngun TC, Ghahramani N, Sánchez FJ, Bocklandt S, Vilain E. The Genetics of Sex Differences in Brain and Behavior. Frontiers in neuroendocrinology. 2011;32(2):227-246. doi:10.1016/j.yfrne.2010.10.001.

Augustine EF, Pérez A, Dhall R, et al. Sex Differences in Clinical Features of Early, Treated Parkinson’s Disease. Nazir A, ed. PLoS ONE. 2015;10(7):e0133002. doi:10.1371/journal.pone.0133002.

Smith KM, Dahodwala N. Sex differences in Parkinson’s disease and other movement disorders. Exp Neurol. 2014 Sep;259:44-56. doi: 10.1016/j.expneurol.2014.03.010. Epub 2014 Mar 28.

City Maps: Anticipated Life Span Compared by Zip Codes

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

“Just when you think it can’t get any worse, it can. And just when you think it can’t get any better, it can.” Nicholas Sparks

And Now for Something Completely Different (Monty Python’s Flying Circus): City Maps is a project supported by the Robert Wood Johnson Foundation (http://www.rwjf.org/en/library/features/Commission/resources/city-maps.html )- “Across America, babies born just a few miles apart have dramatic differences in life expectancy. To improve health we need to improve people’s opportunities to make healthy choices—in the places where they live, learn, work, and play.”

A study examining life expectancy by USA Zip Codes was posted by scientists at Virginia Commonwealth University (VCU) in Richmond, VA; go here to view the site: http://www.societyhealth.vcu.edu/work/the-projects/mapping-life-expectancy.html

To-date the following areas have been mapped: Washington, DC region; New Orleans, LA; Kansas City, MO; San Joaquin Valley, CA; and Minneapolis, MN.  The VCU project is to create maps for 20 new cities and rural areas.  They have compiled results for the following 5 cities: Atlanta, GA; Chicago, IL; Las Vegas, NV; New York City, NY; and Richmond, VA. The over-arching question is why are some neighborhoods healthier than other neighborhoods?

Their data are displayed in maps and tables.  You can enter your own Zip Code, and compare it to your neighboring communities or these other cities in the USA.  Clearly, your question is going to be “Does where you live affect your health and life expectancy?” The VCU researchers commented: “The maps illustrate the vastly different health outcomes experienced by Americans living just a few miles apart and serve as a conversation starter about the social determinants of health.”

My local newspaper highlighted a Zip Code comparison in Raleigh, NC: “Using U.S. Census data and state death records, the researchers calculated that babies born today in ZIP code 27617, which includes the Brier Creek area of Raleigh, can be expected to live to 88, while babies born in 27610, including Southeast Raleigh, are expected to live to only 76. According to Zillow.com, the median home value in the Brier Creek ZIP code is $252,600, while in the Southeast Raleigh ZIP code that value is $129,400.”
“Other studies have found relatively poor health and shorter lifespans in communities of lower income. A difference in life expectancy of only a few years can signal a big discrepancy in public health, said Jim Marks of the Robert Wood Johnson Foundation, which funded the (VCU) study.” (Read more here: http://www.newsobserver.com/news/local/counties/wake-county/article29963712.html#storylink=cpy )

There are neither easy answers nor quick solutions to what is shown the Zip Code and life expectancy study. One step that could help is continued improvement of health education.  However, there are so many other factors that influence our lives, as evidenced in the story being revealed by the VCU study.

“The real things haven’t changed. It is still best to be honest and truthful; to make the most of what we have; to be happy with simple pleasures; and have courage when things go wrong.” Laura Ingalls Wilder

“The saddest aspect of life right now is that science gathers knowledge faster than society gathers wisdom.” Isaac Asimov