Medscape article on Parkinson's

July 10, 2012

Docs:

Interesting Medscape article on the causes of Parkinson's with

implications for farmers. The good news is that mega-3 fatty acids

from fish oil and flaxseed appear to lower risk.

Lyndon McGill, D.C.

EvolvHealth Wellness Advisory Council Member

Salem, Oregon

www.SalemSpineClinic.com

www.EvolvingDaily.com

What Causes Parkinson Disease?

Bret Stetka, MD; Caroline M. Tanner, MD, PhD

Posted: 07/02/2012

Editor's Note:

At the 2012 Annual Meeting of the American Academy of

Neurology (AAN) in New Orleans, Louisiana, Dr. Caroline Tanner

received the Movement Disorder Research Award and presented new

data on the etiology of Parkinson disease (PD). Medscape sat

down with Dr. Tanner the following morning to discuss her work,

the evolving understanding of PD etiology, and therapeutic

approaches with the potential to -- finally -- prevent PD.

What Causes Parkinson Disease? Introduction

Medscape: What is currently known about the etiology of PD,

and what genetic and environmental factors are thought to play a

role?

Dr. Tanner: I think there certainly are 2 factors at

work: genetics and the environment. This becomes more and more

interesting as time goes on, as we recognize the many different

types of interaction between genes and environment.

Classic examples involve the combination of an inherited

metabolic characteristic, such as a detoxification enzyme, and

exposure to a toxicant that is metabolized by that enzyme.

Individuals who are genetically poor metabolizers are more

vulnerable when exposed to the toxicant. In recent years,

scientists have recognized other interactions. For example,

epigenetic changes, such as methylation affecting gene function or

replication, could be caused by environmental exposures.

So it's interesting to see how much both genetics and environment

matter. At this point, it's hard to say whether genetics or

environment is more important, because I don't think we have

enough information yet to be able to tell completely.

We know that there are very rare forms of PD that are strongly

genetically determined. There are a few genes that are almost 100%

penetrant, such as the dominantly inherited mutations in the

alpha-synuclein gene. But these are pretty rare and are only seen

in a few families here and there, usually those with Mediterranean

lineage. But recognizing these forms was really important.

Since recognizing the alpha-synuclein point mutations, we began

to notice that other changes in the gene may also influence PD

risk; people who have duplication or triplication of the normal

nonmutated gene may also develop PD. Clearly, this tells us that

alpha-synuclein protein is important in PD pathogenesis. And then,

people noticed that changes in the promoter region of this gene

could also affect risk, but in this case the genetic change just

serves as a risk factor.

We've just recently published an example of gene/environment

interaction involving the promoter region of the alpha-synuclein

gene.[1] We have known for years that head injury is

associated with a greater risk for PD, but not all people with

head injuries develop PD. Our recent work, presented by my

colleague Sam Goldman, provides an explanation. Depending on your

promoter region variant, your vulnerability to getting PD if you

have a head injury varies. This is one example of the combined

effects of genotype and environment on PD risk.

I think the more we look, the more we're going to find. I think

that almost everything we end up calling a "risk factor" as far as

genes go is likely to also have environmental influences that will

determine whether or not PD develops. Similarly, for almost every

environmental factor, I think the underlying genetic substrate is

important. And it gets more complicated: For many people, there

may be multiple genes and multiple environmental factors working

together to cause PD, and an individual person's risk will be due

to the combined effects of all of these influences.

Medscape: So one day, we could be saying, for example, that

a patient has "x" mutation that puts them at an elevated risk

for PD, coupled with a known environmental exposure, and

therefore they have a certain calculated risk for PD?

Dr. Tanner: Yes. I do think with the current state of

information processing, it will be possible to come up with a risk

quotient. But that's a bit far into the future. People are already

more or less doing this for other complicated diseases, such as

heart disease and diabetes. We tend not to think about this

approach in terms of PD, but if you told someone that their stroke

risk depends on both their genes and their environment, they'd

probably say, "Sure." This is still a relatively new idea in PD.

But we're getting there.

The other important direction for research is to investigate the

extent to which certain risk factors might be easily modifiable.

It's just like with stroke or heart disease: If exercise makes a

positive difference in PD, as data presented at this week's

meeting showed,[2,3] this is a very easy recommendation

for clinicians. It's simple advice, nonpharmacologic, and doesn't

have side effects.

Should You Be Screening Farmers?

Medscape: You presented some interesting exposure data at

yesterday's session.[4] What specific environmental

exposures have been linked to PD?

Dr. Tanner: The chemical MPTP -- one of the most

extensively studied compounds known to induce parkinsonism in

humans -- is a very rare cause of parkinsonism. In the laboratory,

MPTP causes oxidative stress and impairs mitochondrial function.

Paraquat, a commonly used herbicide, is similar in structure to

MPTP. In the laboratory, paraquat also causes oxidative stress and

a Parkinson-like condition in animal models. This prompted several

people to look at whether or not pesticide exposure and

agricultural work might be associated with PD risk.

Big exposure categories, such as pesticide use, began to be

identified, but getting details on specific chemicals was

difficult because it required getting the life histories on the

subjects. This was a bit of an impasse, because there are many

different types of pesticides with very different biological

effects. It seemed unlikely that all pesticides would be

associated with PD.

That's why we started taking detailed occupational histories to

collect pesticide exposures. And we did find paraquat to be

associated with risk for PD in several different populations. One

was an occupational case/control study where there were relatively

few exposed people, but those who were exposed had a 2.5 times

greater risk. Then we went to the farming population, because we

knew they had to keep good records on what chemicals they've used.

Again, we found paraquat to be associated with PD. So this

association is becoming fairly convincing.[5]

The other thing in our recent paper was the finding of an

increased risk for PD associated with rotenone. Rotenone has been

used in research to block mitochondrial complex 1 in the

laboratory for years. It's a naturally occurring compound in

numerous plants, and native people had recognized it to be

poisonous; they would grind up rotenone-containing plants and put

them in the water to stun fish. It's been used in a wide range of

pesticide products over the years -- including household products,

such as flea powders; insecticides for houseplants or gardens; and

home pest removal, as well as commercial products -- so it's hard

to answer the question, "Were you exposed to rotenone?" But by

studying farmers and their spouses, who actually had records on

whether or not and when they used it, we were able to find a

specific association with PD.

A third compound that I didn't talk about yesterday is 2,4-D

(2,4-dichlorophenoxyacetic acid), which is also an herbicide and

is a component in Agent Orange. As we were reporting an

association between occupational exposure to 2,4-D and PD, the

Veterans Administration reported that veterans exposed to Agent

Orange were entitled to disability benefits for PD. Their

determination was based on other information, not on our work, and

they didn't make specific reference to 2,4-D exposure of course,

but it's interesting that we came to the same conclusion through

studying 2 different types of exposure to the same chemical.

I should say that our other study did not show an association

with 2,4-D despite some of the farmers having used the agent, so

these findings still need replication. Also, it is essential for

basic scientists to study the effects of these chemicals

associated with PD in humans in the laboratory, because there's no

incentive for the pesticide manufacturing industry to identify new

adverse health effects of pesticides. Their interest is in

figuring out whether or not a compound kills the pest. And unless

they're told to, they're probably not going to be doing studies on

adverse health effects. So, we need scientists to be looking at

these chemicals in the laboratory.

Diet, Treatments, and Advice to Patients

Medscape: Have there been any dietary associations with PD,

positive or negative?

Dr. Tanner: Yes. My colleague Freya Kamel just reported

that polyunsaturated fatty acids (including omega-3 fatty acids

found in fish and certain plant and seed oils) are associated with

a lower risk for PD.[6] These counteract oxidative

stress, one of the mechanisms that's thought to be critical in the

pathogenesis of PD. So, certain environmental factors can have a

positive effect as well; these are important to identify, because

they're an easy recommendation. It's too bad flaxseed is not so

palatable!

Other people have looked at the Mediterranean diet and found it

fairly beneficial in Alzheimer disease, and one report shows the

same in PD.[7] Also, diets that are high in certain

antioxidants and diets that tend to increase the level of the

strong antioxidant uric acid are associated with a lower risk for

PD. Conversely, dairy products or diets high in animal fats were

associated with greater risk for PD.[8]

Medscape: Beyond potential dietary recommendations,

what advice do you have for community neurologists or primary

care providers in terms of minimizing risk? Are there genetic

tests available that you would recommend for at-risk patients?

Dr. Tanner: Genetic testing for PD is a little

controversial at this point. There are a few genes that are more

common, and some people might want to be tested for them, such as

people with a strong family history of PD. But in that case, I

strongly advise the involvement of a genetic counselor, because in

most cases having a mutation associated with PD does not

necessarily mean that the individual will ever develop PD.

For example, mutations in the LRRK2 gene can account

for a significant number of PD cases in certain populations –

Mediterranean, Ashkenazi Jew, and North African. So here you might

say that there could be some justification, particularly in

familial PD but also maybe even in nonfamilial, to test for

mutations in the LRRK2 gene.

But whenever you do this, it's not just the individual being

tested that you're concerned about, but also the family. Patients

have to seriously think about how to address this with their

family members, particularly if some members of the family don't

want to know their own genetic status.

And it's particularly important, because this gene is not fully

penetrant -- so having the gene does not necessarily mean that you

will definitely develop PD. Just being able to know that you have

a mutation might not be so good.

On the other hand, some people do want to know. People who know

that their genotype may put them at risk for PD may be motivated

to live healthier lifestyles. In this case -- as we touched on --

there are a few recommendations you can make as a clinician that

are probably good things to do. And even if they're not completely

accepted as being beneficial in PD, they're probably good things

to do anyway: for example, exercising and eating a healthy diet.

We do not at this point have a treatment that has been

demonstrated to alter the course of PD. Throughout my career,

we've been trying to develop one, but we still don't have one.

Having one would certainly change the game, and we'd potentially

be able intervene early. Having an effective way to delay or

prevent PD might make many people more interested in knowing

whether they carry a risk mutation.

As I mentioned in my talk, we're not quite sure whether the

treatments we have are not good enough to alter the disease, or

whether most cases of PD have progressed so far by the time we see

them that the current treatments are ineffective. Throughout most

of my career, we have been interested in identifying people at

risk for PD at the very earliest point.

I believe that we will be able to prevent PD with new

understandings and ways of identifying people at risk, possibly

through biomarkers. I envision a screening approach comprising

several different ways of identifying someone who might be at risk

for disease. For example, persons with loss of olfactory function,

or those with REM sleep behavior disorder or a specific mutation,

might be identified at the first level of risk. Then you'll bump

them to the next level of testing -- maybe dopamine transporter

imaging, or maybe a biomarker test -- and if they look like they

might be at risk on the basis of these tests, you can monitor more

closely. Of course, if we had an effective intervention, that

would be the time to use it -- before the parkinsonian symptoms

have developed. So in the future, when people of a certain age get

screened for colon or breast cancer, we could also screen them for

neurologic diseases, such as PD.

Medscape: So at this point, even if your patient was

found to be predisposed to PD on the basis of a genetic test or

has been exposed to known environmental risk factors, for now

clinicians should focus on lifestyle advice?

Dr. Tanner: For now. But there is one other analysis we

did in the study of farmers and their wives, which was to look at

who wore personal protective equipment. Some wore respirators, and

some just gloves that were impervious and a coverall. People who

used protective equipment and washed off after spills did not have

an increased risk for PD. So I think the basic, healthy living,

common-sense approaches are very important.

Medscape: And this seems like something primary care

physicians should be aware of?

Dr. Tanner: That's right. If you are a primary care

physician in a farming region, it would be worthwhile to have this

talk with your patients. And the same goes for those who work in

industrial settings with potential solvent exposures.

And Finally, Treatments

Medscape: What potentially disease-modifying agents

are under investigation for PD at the moment? Is the

free-radical hypothesis still a focus?

Dr. Tanner: It is, yes.One of the compounds being

looked at is an agent that elevates uric acid -- not to the gout

range, but to high-normal -- because we found that uric acid is

inversely associated with risk for PD and also slows PD

progression. There's a similar observation that people taking

calcium-channel blockers may have a lower risk for disease, so

there's a trial ongoing, with the results coming soon.

Other trials have failed to provide unequivocal evidence of an

effect on PD progression. There's the selective irreversible

monoamine oxidase B inhibitor selegiline, which blocks MPTP, and

rasagiline, which has a similar mechanism of action; rasagiline

did not receive an indication from the FDA for neuroprotection.

Coenzyme Q10, which directly affects the mitochondria,

was also recently found to be ineffective.

There's also an ongoing trial on creatine, which also affects

mitochondrial function. Finally, a strong inverse association

between smoking and PD has been known for decades, and there's a

nicotine study starting this year.

Medscape: So, what's next for you and the Parkinson's

Institute?

Dr. Tanner: A lot of people investigate genes because

it's sexy; the technology gets better and better, and more genes

can be identified more quickly and at lower cost with each

technological advance. Environmental influences are not easy to

assess, and when lifelong exposure information is needed, our

current methods involve taking lifelong histories -- no dazzling

technology. But we're trying to come up with an equal-opportunity

measurement for environmental influences.

One approach is to look at a biomarker: the adverse effect of

environmental exposure. For example, I am working with Tim

Greenamyre at the University of Pittsburgh, who's developing a

marker for impaired mitochondrial function that can be determined

with a blood test. We're going back to several of our exposed

populations to see whether we can use this marker to identify

those who were exposed, either with PD or possibly at risk. This

could be immediately applicable in an industrial or occupational

setting.

We also hope to extend our screening to investigate people who

may be at risk for PD owing to environmental exposures. Now we

want to look at people who were exposed to environmental factors

associated with an increased risk for PD but don't have disease,

to see whether they're exhibiting any pre-Parkinson symptoms, such

as impaired olfaction or autonomic nervous system dysfunction.

These people, just like those with genetic risk factors, may

benefit from lifestyle changes associated with lower risk for PD

or, in the future, treatment with a preventive therapy.

I have a public health background, so the bottom line is, I want

to prevent this disease.

References

Goldman SM, Kamel F, Ross GW, et al. Head injury,

á-synuclein Rep1, and Parkinson's disease. Ann Neurol.

2012;71:40-48. Abstract

Gou P, Chouinard S, Jodoin N, Diab S, Panisset M. Effect

of exercise on the clinical progression of Parkinson

disease. Program and abstracts of the 64th Annual Meeting

of the American Academy of Neurology; April 21-28, 2012;

New Orleans, Louisiana. Abstract IN6-1.004.

Corcos D, Robichaud J, F. 24 months of exercise

improves the motor symptoms in Parkinson's disease.

Program and abstracts of the 64th Annual Meeting of the

American Academy of Neurology; April 21-28, 2012; New

Orleans, Louisiana. Presentation S02.003.

Tanner C. Presentation of the movement disorder research

award. Program and abstracts of the 64th Annual Meeting of

the American Academy of Neurology; April 21-28, 2012; New

Orleans, Louisiana. Presentation S02.

Tanner CM, Kamel F, Ross GW, et al. Rotenone, paraquat,

and Parkinson's disease. Environ Health Perspect.

2011;119:866-872. Abstract

Kamel F, G, Umbach D, et al. Risk of

Parkinson's disease (PD) associated with the herbicide

paraquat is attenuated by high dietary intake of

polyunsaturated fatty acids (PUFAs). Program and abstracts

of the 64th Annual Meeting of the American Academy of

Neurology; April 21-28, 2012; New Orleans, Louisiana.

Presentation S42.004.

Alcalay RN, Gu Y, Mejia-Santana H, Cote L, Marder KS,

Scarmeas N. The association between Mediterranean diet

adherence and Parkinson's disease. Mov Disord.

2012;27:771-744. Abstract

Gao X, Chen H, Choi HK, Curhan G, Schwarzschild MA,

Ascherio A. Diet, urate, and Parkinson's disease risk in

men. Am J Epidemiol. 2008;167:831-838. Abstract

July 10, 2012

Lyndon, Adding coconut oil and it's saturated state works effectively ... put the two together to lower the free radical content of the brain tissues. SunnySunny Kierstyn, RN DC Fibromyalgia Care Center of Oregon 2677 Willakenzie Road, 7CEugene, Oregon, 97401541- 654-0850; Fx; 541- 654-0834www.drsunnykierstyn.com To: oregondcs From: twogems@...Date: Tue, 10 Jul 2012 18:04:04 -0700Subject: Medscape article on Parkinson's