KosAbility: Parkinson's and Pesticides

Introduction

The classic signs of Parkinson’s disease are tremors and other motor problems. Parkinson’s also affects other parts of the body. We will take a look at what Parkinson’s disease is, how people get it, and how, hopefully, to avoid it.  For the less lucky, how symptoms are treated, and how progression can perhaps be halted and even reversed.  We want to stop disease progression if we can, and the sooner the better. The early warning signs are usually missed – so we need to know what they are.  That’s our roadmap for today.

What is Parkinson’s

Parkinson’s disease is characterized by the inability of the body to properly recycle a protein called alpha-synuclein.  Instead of being broken down, this alpha-synuclein is deposited in microscopic clumps known as Lewy bodies.  Lewy bodies have been found in the brain, salivary glands, olfactory system, skin, and colon.  Lewy bodies are not themselves the cause of the Parkinson’s disease impairments, but they are a marker signifying the underlying metabolic defect.

When we think of Parkinson’s we think of motor problems. In early Parkinson’s this manifests as tremors, later on, in advanced Parkinson’s, there is shuffling gait and freezing. These motor problems are due to a lack of dopamine, resulting from the destruction of dopamine-producing neurons. They are located in an area of the brain known as the substantia nigra (dark matter). Treatment consists of various measures to remedy the resulting dopamine deficiency. The involuntary jerks and twitches that afflict some patients, such as Michael J. Fox, are known as dyskinesias, and are an adverse response to unregulated dopamine that occurs in patients with long-standing illness.

The dopamine producing neurons are not the only cells of the body affected by Parkinson’s disease but they are usually the first to go because they are extremely vulnerable.  They are very energy intensive, and typically contain 1000’s of mitochondria. A single dopamine neuron’s axon may have over a million branches with a combined length of over ten feet. They can be impaired or destroyed by wide variety of toxic substances as well as certain forms of brain damage. The resulting symptoms in such cases are similar to Parkinson’s and are called parkinsonism.  If the other neurons go first, the resulting ailment may be referred to as Lewy body dementia or multiple system atrophy.

Parkinson’s can cause a wide variety of impairments.  A partial list: 

• Additional motor problems include painful and contracted muscles. The medical term for this is “stiffness” which is an understatement.  
• Day night sleep reversal:  Ordinary insomnia is about feeling tired and wanting to sleep but unable. Day-night sleep reversal is about being wide awake at night and having involuntary sleep attacks during the day. 
• Fatigue: a common symptom even if the patient is able to sleep
• Parkinson’s disease dries out the GI tract from one end to the other.  At the top end inadequate saliva, at the bottom, dry stools and constipation.

What causes Parkinson’s disease?

The study Occupation and Risk of Parkinsonism surveyed the odds of acquiring Parkinson’s symptoms versus selected job tasks:

TASK	ODDS RATIO*
Pesticide use	1.9
Woodworking	1.49
Gluing	1.31
Stripping	1.3
Industrial painting	1.18
Household painting	1.11
Soldering	1.05
Cleaning	1.01
Welding	1.01
Machining	0.93

(*Odds Ratio describes the likelihood of two events being associated, in this case the observed rate at which someone engaged in the named task was subsequently diagnosed with Parkinson’s, relative to the rate of the population at large.   This is not proof one causes the other as the relationship could be due to a third factor that causes both.  In the case of pesticides, there are numerous animal studies that demonstrate causation, which for obvious ethical reasons cannot be done using humans.)

The risk of Parkinson’s disease associated with pesticide use clearly exceeded the other tasks surveyed.  They also looked at specific pesticides:

Exposure	Odds Ratio	p value*
Pesticide use, any	1.9	0.02
2,4-Dichlorophenoxyacetic acid	2.59	0.04
Paraquat	2.8	0.1
Permethrin	3.21	0.15
Dieldrin	1.3	0.77
Diquat	1.02	0.99
Mancozeb	1.01	0.99
Rotenone	0.82	0.89

(*P value is the likelihood the result was arrived at by chance. In general, p less than .05 is considered meaningful, although different study designs have different thresholds.)

Permethrin is a pyrethroid, a relative of pyrethrum, a natural insecticide produced by chrysanthemums.  This has until now been regarded as non-toxic to humans.  For that reason they are commonly found in insecticides for home use. This study was not specifically aimed at permethrin, or insecticides, so the p value did not reach statistical significance due to a small number of cases.  So let’s now take a look at studies that looked specifically at pesticides.

Protective glove use and hygiene habits modify the associations of specific pesticides with Parkinson's disease

“Pesticides have been associated with Parkinson's disease (Parkinson’s disease), and protective gloves and workplace hygiene can reduce pesticide exposure. We assessed whether use of gloves and workplace hygiene modified associations between pesticides and Parkinson’s disease. … Protective glove use modified the associations of paraquat and permethrin with Parkinson’s disease: neither pesticide was associated with Parkinson’s disease among protective glove users, while both pesticides were associated with Parkinson’s disease among non-users … permethrin OR 4.3 … p = 0.05.”

In other words, workers who used protective gloves did not have an elevated risk of Parkinson’s, versus workers who did not use protective gloves and handled permethrin had increased odds of acquiring Parkinson’s by a factor of 4.3, and that result was statistically significant.

Additional findings:

“Rotenone was associated with Parkinson’s disease regardless of glove use. Trifluralin was associated with Parkinson’s disease among participants who used < 2 hygiene practices (OR 5.5 …) but was not associated with Parkinson’s disease among participants who used 2 or more practices.” So stay away from rotenone and trifluralin.  Trifluralin is also a pyrethroid.

Here’s a study that looked at the interaction between a common genetic variant and exposure to pyrethroids.

They found for a particular genetic makeup: “comparing those homozygous for the risk allele (GG) and exposed to pyrethroids to those with the AA genotype and unexposed, we see an increased risk of Parkinson’s disease … OR=2.48”

Home Use

Here are the directions for a typical permethrin home insect fogger.

Cover or remove all food related items, surfaces and children’s toys, stay out of the area during treatment and until the treated area has been thoroughly ventilated. Wait two hours after treatment, ventilate for another two hours. Then you are good to go.  For a treatment that was considered to be non-toxic this would be sufficient.  Too bad that is not the case.

Given the wait times specified above you might think that permethrin was not persistent.   If so you would be wrong. Various studies of permethrin half life in soils have yielded half lives ranging from 11 to 36 days.  In cropland soils we have bacteria, fungi, nematodes and plant roots all actively participating in soil chemistry, unlike interior surfaces of a home. So the half-life of permethrin in the home is easily two weeks, and likely a lot more. Moreover after one half life the levels have only decreased by – half.  So exposure will continue over many half lives. 

You may have covered all the food surfaces but there is permethrin residue on the floors, walls and furniture, and its going to be there for months.  The concentration is not very high but that is a long time.  This is most likely how I got Parkinson’s

We have focused on permethrin because that is commonly used inside the house.  Here are the results from some studies of additional insecticides :

Study	Year	n	Location	Design	Exposure	RR*
Liou	1997	65	Taiwan	Case-control	Paraquat	3.2
Kamel	2007	63	USA	Nested	Paraquat	1.8
Hancock	2008	73	USA	Family-study	Organochlorines	2
Gatto	2009	70	USA	Case-control	Diazinon	1.6
					Chlorpyrifos	1.5
					Propargite	1.3
Tanner	2009	66	USA	Case-control	Paraquat	2.8
					Permethrin	3.1
					2,4-D	2.6
Elbaz	2009	74	France	Case-control	Organochlorines	2.4
					Rotenone	2.5
Tanner	2011	55	USA	Case-control	Paraquat	2.5
					Dieldrin	1.6

*RR = Risk ratio “is the ratio of the probability of an event occurring (for example, developing a disease, being injured) in an exposed group to the probability of the event occurring in a comparison, non-exposed group.”  Permethrin is right up there with the notorious paraquat with a RR over 3.

Source: Environmental Toxins and Parkinson’s Disease

Parkinson’s Treatment

The characteristic deficit of Parkinson’s disease is lack of dopamine, and so the first aim of Parkinson’s disease treatment is the care and feeding of dopamine. To this end there are three types of meds:

1. Dopamine replacement: Carbidopa/levodopa is a combination that gets levodopa across the blood-brain barrier into the brain, where it is converted to dopamine.  There are various brands such as Sinemet and Rytary.  Some doctors have mistakenly advised patients to delay use of this type of medication based on the belief that usage causes intolerance.  That has now been shown to be incorrect by a recent study of patients in Ghana, some of whom did not have access to this type of medication for a very long time.  The study demonstrated that length of usage bore no relation to subsequent intolerance, which is a result of long standing Parkinson’s disease.  The real reason for late stage levodopa intolerance is earlier in the disease there are still neurons producing dopamine, so it is still possible for them to regulate their output of dopamine in response to need.  Late in the disease these are gone and the internal ability to regulate dopamine is lost.
2. Dopamine conservation:  MAO-B inhibitors slow the rate at which dopamine is broken down by native enzymes.  Azilect (rasagiline) and seligilene have been in use for a while and now in Europe there is newly approved Xadago® (Safinamide).
3. Dopamine sensitization: Drugs known as Dopamine Agonists (“DAs”) stimulate dopamine receptors.  They must be titrated for each patient to provide enough background stimulation to make nerve cells more sensitive to dopamine without overstimulating them. There are significant downsides to DAs:
   1. Impulse control disorders (“ICDs”):  ICDs refer to compulsive gambling, shopping, sex, or eating.  ICDs “were more common in patients treated with a dopamine agonist than in patients not taking a dopamine agonist (17.1% vs. 6.9%; odds ratio … 2.72)”. Some patients who have been previously responsible citizens have ended up losing everything as a result of ICDs. To make matters worse, some of these patients also end up suffering from Dopamine Agonist Withdrawal Syndrome. In such cases attempted withdrawal from these meds results in overwhelming depression.
   2. Orthostatic Hypotension (“OH”):  This refers to an inability of the autonomic nervous system to adjust heart rate and vascular tone to compensate for changes in posture. Upon standing, patients with OH suffer a loss of blood perfusion to the brain and are prone to fainting. A recent study found that 30% of Parkinson’s disease patients developed symptoms of OH upon their very first, low, dose of a DA. Such patients must not take DAs.  There have been instances of patients suffering long term or even permanent OH after a DA is withdrawn.

DAs are also prescribed for restless leg syndrome.  There are a number of them: Bromocriptine / Parlodel, Cabergoline /Dostinex, Pergolide / Permax, Pramipexole / (Mirapex), Quinagolide / Norprolac, Ropinirole /Requip, Rotigotine / Neupro.  In view of the foregoing it is apparent that these are dangerous drugs. They should only be tried after the other alternatives have proven inadequate.  Unfortunately doctors will not necessarily warn us about the adverse effects of such medications. See KosAbility: When Good Doctors Prescribe Bad Medicine for more detail on that subject.

Parkinson’s Reversal

The foregoing medications relieve Parkinson’s disease symptoms.  Ideally we would like to halt progression and reverse the damage.  This seemed like a faint hope until the over last year, two promising treatments have been documented.

            A phase 1 trial of the leukemia drug nilotinib made national news last year when late stage Parkinson’s patients who were in wheelchairs were reported to have recovered the ability to walk, those unable to speak became able to talk, etc. At trial’s end patients were reported to be hocking assets in order to be able to continue taking the drug which costs thousands per month.

The trial has been criticized for allowing such publicity because it was only a phase 1 trial without a control group. Parkinson’s is very interesting in that in Parkinson’s disease the placebo effect is therapeutic — positive expectations cause the release of dopamine. So upon visits to doctors offices Parkinson’s disease patients have improved so dramatically caregivers have wondered if they were faking their symptoms. 

            There is a fellow named John Pepper who has Parkinson’s and tours the world sharing his techniques for overcoming the Parkinson’s disease impairments, asking only for his travel expenses.  Just last week he posted this: “At yesterday's talk in Marin County CA, there were quite a few tears, including mine, when I was able to get a patient up out of his wheelchair and within a minute or two he was walking beside me through the hall. Yes! Exercise is the answer to Parkinson’s disease, until we get that elusive cure!”

            Now that may not have been placebo effect but the point is that Parkinson’s is a curious mixture of mind and matter.  For a long time I thought the shakes in my arm were merely a way of holding nervous tension because it got worse when I was stressed and I could stop them via conscious attention.  There are cases of patients attributing their symptoms to nerves until very late in the disease.

            Back to nilotinib – it seems likely the effects are real because the improvements seem to be durable over long periods of time.  There are sound biochemical reasons to believe it should work — via a complicated dance of molecular signaling it prompts cells to resume reprocessing the alpha synuclein protein. Its efficacy has been demonstrated in the lab with mice and in cell cultures are not subject to placebo effect.

            Unfortunately there are some serious downsides in addition to cost.  Some leukemia patients taking it have suddenly dropped dead.  This is thought to have been due to lengthening the Qt interval in the heart.  Patients are now screened for vulnerability to this.  The other problem with nilotinib is skin rash – up to 47% of patients have been reported to have skin rash in reaction to nilotinib, and in some cases it has been quite severe. For patients who can tolerate nilotinib and afford it may be a good solution.

NAC

Fortunately there is another choice: N-acetylcysteine, also known as NAC. Wikipedia:

N-Acetylcysteine:

is the N-acetyl:

derivative of the amino acid L-cysteine:

The thiol (SH) group confers antioxidant effects and is able to reduce free radicals.  L-cysteine is a precursor to the biologic antioxidant glutathione. Hence administration of acetylcysteine replenishes glutathione stores.

“Glutathione (GSH) is an important antioxidant in plants, animals, fungi, and some bacteria and archaea. GSH is capable of preventing damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides and heavy metals.^”

NAC is very interesting. It is used in inhaled form for mucolytic (mucus-dissolving) therapy in respiratory conditions with excessive and/or thick mucus production.  In IV form it is used as an antidote to acetaminophen overdose.  It has been found to ameliorate prostatitis.

In June of this year a study entitled:

“N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson's Disease: Preliminary Clinical and Cell Line Data” was published in Plos One.

The study showed that NAC was protective of dopamine producing nerve cells upon challenge by insecticide (rotenone).  It also showed that after three months of treatment, humans treated with NAC increased production of dopamine in their brains, and their symptoms improved.  These results were statistically significant in comparison to a control group.  This was not a blinded study so these results will need to be confirmed. Meanwhile…

NAC is available as an over the counter supplement for pennies per dose.  I started taking it soon after becoming aware of the study.  After several weeks I paid a visit to my dental hygienist who commented that she did not notice any tremors while working on me, unlike prior occasions (some other symptoms have been on the increase, unfortunately).  Comments from some other users in a Parkinson’s forum:

“I'm having good results with NAC. My left side has improved significantly in terms of strength. At first I thought I was imagining it, but I'm not. I've been keeping a diary.”

“I am testing this and after 20 days believe it is working so far. Will give it a bit longer before getting too excited, but the other day my foot just relaxed all on its own!!”

So NAC seems to work. If these results continue to be borne out people with early stage Parkinson’s disease will want to start taking it as soon as possible to prevent progression of the condition.  Which brings us to…

Initial Symptoms

In retrospect I had Parkinson’s disease symptoms years before I was actually diagnosed. This is not uncommon.  My earliest symptom was cramping of the 3^rd & 4^th toes of my left foot.  Michael J. Fox’s first symptom was his pinky — when he first noticed his little finger shaking, he put it down to a hangover.

Later on I developed a habit of holding my left arm in a position called by some Parkinson’s patients the “purse carrying” position.  Pills would get stuck partway down my esophagus which I now realize was due to loss of lubrication. Insomnia is another sign. I never said: “My god, these disparate symptoms are all signs of dopamine shortage!”  I had no idea.

Tremors in my left arm.  Over the course of a couple of a couple years I brought that to the attention of three different doctors.  They should have recognized it but did not.  That should not have been good enough and I should have taken further action – but early diagnosis would have done me no good at the time. Finally, when I started dragging my left foot, I got myself to the neurologist, who diagnosed classic Parkinson’s disease.

Some additional Parkinson’s disease symptoms are: developing small handwriting, soft voice, loss of sense of smell, constipation, and low blood pressure.

Well, that’s all folks.  I’ll leave you with this recent performance by rock star Michael J. Fox:

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