Old Drugs – New Cures?

From James Beck, Ph.D., Vice President of Scientific Affairs

Using old drugs as new cures seems like a surefire winner. It may be. However, after attending a recent meeting outside London hosted by the Cure Parkinson’s Trust, a small yet impactful British charity, it is clear that this path is neither clear nor easy. A committee of experts at the meeting evaluated and prioritized dozens of existing compounds – many are drugs used to treat other diseases – based upon their potential to stop Parkinson’s disease.

From left, James Beck, Tom Isaacs, and Steven DeWitte at
Cure Parkinson's Trust meeting at Cumberland Lodge.

Repurposing drugs for a new use like this has the potential to shave significant time from the drug development process for Parkinson’s. But existing drugs come with existing problems. And these problems cannot always be overcome. For instance, a recent science article covered by PDF suggested that a chemotherapeutic agent, nilotinib, might be useful for treating PD. However, it is not clear what the proper dose should be (the article suggested a low one would be effective). Moreover, with potential side effects that include sudden death, the committee felt it was not ethical to consider placing people living with PD in potential danger.

Still, there are drugs that appear to be safe and well tolerated, like statins used to lower cholesterol and metformin used for type II diabetes to name a few. These drugs are not chosen at random: By surveying thousands of people, epidemiology studies have been able to link drugs people take for other conditions (like these) with a lower risk of developing PD. There are also data from laboratory studies that suggest how these types of drugs may help. Even here, though, the path forward is not so clear. The mechanism of action, that is how might some of these drugs actually affect PD in people, is not known. This is not always a stumbling block; but when combined with drugs that are likely to have modest effects and low odds of success, it can be a problem, especially with limited resources.

Recognizing these issues, the Trust’s prioritization committee took a hard look at each potential drug candidate and recommended a handful as most promising. These few culled from a list of two dozen compounds will now advance towards evaluation in clinical trials. Hopefully, that phase will begin soon.

BigBrain - What Does It Mean?

From James Beck, Ph.D., Vice President of Scientific Affairs

This blog is part two in a series of three about the BigBrain.

Several weeks ago saw the announcement of a description of a new and highly detailed atlas of the brain, called BigBrain.  PDF wrote about how one person, making the decision to donate their brain, has made a significant contribution to science.  Indeed, that is true.  But what does this really mean for the future of neuroscience … and Parkinson’s research?

1. BigBrain is like the Google Earth of the brain, allowing researchers to not only see the big picture of brain anatomy but also allowing them to zoom in with incredible resolution to practically see individual cells.
2. Although BigBrain is like Google Earth, it currently does not have any labels.  That is, if you do not already know what you are looking at, BigBrain will not be able to help you.  (Is that New York City or Jersey City that I see?) Not all scientists are experts in neuroanatomy and so not everyone looking at BigBrain can delineate every brain structure.  Besides, annotating BigBrain will only need to happen once.  As this is done over time, researchers of all stripes will be able to ask interesting questions.
3. BigBrain is helpful, but it's just that: one person’s brain … Just like the first genome sequenced in the Human Genome Project was just one person’s DNA.  Half the battle here has been establishing the procedures to actually create a BigBrain.  As more courageous individuals donate their tissue, scientists will be able to generate more BigBrains in order to capture all the individual variation that is in each of our heads.

In sum, BigBrain is what they call “enabling technology.”  On its own it does not do much, but when combined with other technologies it is a powerful tool that can move science forward.  Thinking what the personal computer or the Internet have done recently, it will be exciting to see how this will change neuroscience.

(A view from the BigBrain atlas. The substantia nigra, where dopamine neurons are lost in PD, are the dark bands located below the two dark circles in the center.)

Of Patents and Parkinson's

From James Beck, Ph.D., Director of Research Programs

Should or could a human gene be patented? On June 13th, the Supreme Court of the United States delivered their unanimous ruling regarding what has been called the Myraid Genetics case.  The plaintiffs in this case sought to invalidate Myriad’s patent on two genes that when mutated can lead to a significant increased risk of breast and ovarian cancers.  Because of the patent for these two genes, Myriad, a clinical diagnostic testing company, was the only entity that was permitted to perform the clinical tests that can both inform women if they carried mutations in these genes and if they are at an elevated cancer risk.

In their ruling, the Supreme Court concluded that naturally occurring genes, like the ones in the patent held by Myraid, are a product of nature and therefore are not eligible for patent protection.

The emphasis of the Court is on naturally occurring genes and that is important because the Court made clear that almost any modification to that naturally occurring gene would be eligible for patent protection—provided it met all the regular standards of a patent.  The example the Court provided was for the ‘cDNA’ sequence of a gene.

When a Gene is Not Natural
So what is cDNA anyway?

It may helpful to think of the genes found in most animals as magazine stories. These stories are constantly interrupted by advertisements, forcing them to span dozens of pages instead of just a few.  These interruptions to the gene story are called introns and, just a like a real magazine story, they get skipped by the body as it reads the gene when making a protein in a process called transcription.  In the laboratory, this “ad-free” or more precisely “intron-free” version of the gene can be converted back to DNA (the cDNA) for later use in a biotech setting.  Because this edited version of the gene did not appear in nature, it is eligible for patent protection.

What Does This Mean?
In general, this decision will not really affect much in the normal operation of science and business.  Whenever a gene is patented, the ad-free cDNA version is almost always included as part of that patent.  Importantly, it is this cDNA version that is really of the utmost value to a company because the naturally occurring sequence is often so large and unwieldy it is not practical to use—this is because the cDNA form can easily be just one-fifth the size of the naturally occurring gene. That is a lots of ads that were cut!

For companies that have a product that relies almost exclusively on the naturally occurring sequence, say for a diagnostic test, this ruling will be more disruptive.  In fact, several competitors have just announced that they will offer the same cancer gene test for less than what Myriad charged.

Ok, so what does this mean for Parkinson’s disease?
Again, not much really.  There are several companies that have been trying to develop gene therapies for treating Parkinson’s.  While the patents these companies may hold on the naturally occurring gene sequence is likely not enforceable anymore, the shortened version of the gene still has a valid patent and that is what counts—it is this shortened form that is actually used in the experimental therapy.

While the Court’s ruling that naturally occurring genes are not patentable is certainly historic, I think the initial effects are relatively limited, especially for Parkinson’s.  Time will tell how this ruling will be applied to other areas of intellectual property law.

Vitamin D...Again?

From James Beck, Ph.D., Director of Research Programs

A recent paper published in the American Journal of Clinical Nutrition and picked up by the popular press provided some provocative evidence that vitamin D may provide a short term benefit to some people living with Parkinson’s disease.  PDF has covered the science regarding vitamin D for some time, for example in articles featured here and here.

While the importance of vitamin D in people with PD is not new—most people with PD have too low a level—this paper now suggests that only some individuals may benefit from raising vitamin D levels.  The paper's authors hypothesize that those few individuals have a variation in a protein that binds to vitamin D. They may respond better than others when their vitamin D levels are raised, which may result in a slower progression in disease symptoms.  However, even the authors were notably cautious in their interpretation saying, "vitamin D supplementation may stabilize PD for a short period in patients [with the protein variation], although this effect may be nonspecific for PD."


That is, this study may help explain why vitamin D is not the cure-all for Parkinson’s as some less reputable sources may claim.  Whether this conclusion will stand the necessary scrutiny of continued research is unknown.

What I do know is that good nutrition is important for good health, especially if you have a chronic disease like Parkinson’s.  It is probably worthwhile to have your physician check your vitamin D levels at your next physical—I did.  Maybe like me, you may find out you have low levels of vitamin D. On my doctor’s advice, I now take a few vitamin D pills.  I am not expecting much, but I think it a good idea.  Like checking the tire pressure on your car: it is a little thing that will play a small role in hopefully making your journey through life a bit easier.

For more information on nutrition and PD, read PDF’s Fact Sheet on Nutrition or watch PDF’s PD ExpertBriefing on Nutrition.

Genetic Testing and You

From James Beck, Ph.D., Director of Research Programs

The genetic testing company 23andMe recently announced that it had reached its goal of enrolling 10,000 people with Parkinson's into its genetic testing program. I personally think that is fabulous.

While genetic abnormalities that lead to Parkinson's disease are rare, finding these cases has been a boon to understanding PD for all. From the location and then discovery of the first PD gene by PDF’s first supported fellow, Roger Duvoisin, M.D., and his colleagues in 1996 to the more recent genetic discoveries of today, PDF steadfastly supports research into understanding how genetics and PD interact.

As we move forward, genetic testing is becoming more sophisticated and cheaper too as the cost drops faster than comparable advances made in computing technology. This is akin to buying the original IBM PC desktop one day and then next year being able to bring home the latest iPad. 

Low costs are making genetic testing more ubiquitous and that is causing some problems. For scientists, the problems are a bit academic—they are drowning in data. For the PD community, these problems hit closer to home. Genetics testing has the potential to bring forth knowledge that before was unknowable—the future. The question now is are we ready?

Deciding to voluntarily undergo genetic testing is a very personal decision; and, like many other endeavors, it is not always happy sailing. This is why, in response to the many questions and concerns PDF has received about genetic testing, PDF tasked our Medical Policy Committee to provide guidance for those interested in gene testing.  

Why does this matter? Let me tell you the story I heard about a person with PD who decided to buy a gene test kit  This person wanted to see if he had a genetic cause to his disease.  Not surprisingly, the answer was no; he did not have a mutation in the few PD genes that are examined on a consumer level. However, he got more than he bargained for and what he did find out was not good. In his DNA were two copies of the bad variant of the APOE gene. He now knew he was at a 10-fold increased risk of developing Alzheimer’s disease—information he did not want nor was he prepared to know.

Fortunately, most scientific studies involving gene testing do not reveal the results to those who participate. Providing a blood sample for PD research remains a very easy way for everyone to become participants in the research process, moving us all closer to finally tackling this disease. 

As it stands today, nearly 90 percent of the people with PD do not have a clearly attributable genetic cause to their disease. Since consumer testing only looks at a handful of the known PD genes, the odds of using a consumer test to unveil a personal PD-genetic link are rare. And for those who do, that knowledge will not affect their current medical care. The bottom line with genetic testing is to look before leaping. Take the time to understand what you are buying and deciding what that knowledge is worth to you.

• PDF Direct-to-Consumer Statement
• PDF Genetics PD Expert Briefing - "What's New in Genetics and PD?"

Vascular parkinsonism

From James Beck, Ph.D., Director of Research Programs

Recently, former President George H.W. Bush revealed in an interview with PARADE Magazine that he has vascular parkinsonism.

While not meeting the criteria for true Parkinson’s disease (PD), vascular parkinsonism mimics many features of PD.  As its name implies, vascular parkinsonism is often due to problems with the vessels in the brain regions that control movement and small strokes are the primary cause.  Although small strokes will cumulatively worsen the symptoms of vascular parkinsonism, it is otherwise not considered a progressive neurodegenerative disease like PD.

People with vascular parkinsonism often experience a “lower body parkinsonism” and have trouble with walking and maintaining balance – much like people with classic Parkinson's.  President Bush reports that he experiences such symptoms.  Generally, people with vascular PD are less likely to have the tremor of Parkinson’s disease.

Because the cause of vascular parkinsonism is fundamentally different from true PD, people do not always respond well to the current Parkinson’s disease medications.

Like all people who struggle with a neurological disease, President Bush has many obstacles to overcome.  Because his disease can mimic true PD, his story emphasizes the importance of getting an accurate diagnosis from a movement disorders specialist in order to best manage one’s disease.  PDF maintains a nationwide list of movement disorder specialists and encourages you to call (800) 457-6676 or email us at info@pdf.org to find one in your area.

Grant Review at PDF

Today is a big day for many at PDF — it is our annual grant review. Of course, those most affected by what goes on in the big conference room will not be there. There are two groups who depend on tomorrow's outcome: the scientists who have given us their best ideas for our scientific advisors to judge and the people who live every day with Parkinson's and are counting on these great ideas to make a difference in their disease and their lives. I am confident that the team of scientists helping — members of our scientific advisory board and other experts from around the country — will select only the best science today.

All in all, nearly 25 reviewers have pitched in their time to help whittle down the 200 letters of intent to 63 full grant proposals to, now, only the top 20 or so grants. Because of time, it is these top 20 applications that will actually get discussed.

And for the second time, PDF is doing what no other PD organization in America is doing—making certain those people living with PD have a literal seat at the table and participate in the decision making process. These people, PDF's Research Advocates, part of the Parkinson's Advocates in Research program, insure what we will fund is not just the best for science's sake but for the sake of people too. Something in which we, as an organization, take great pride and you as a community should too.

Tomorrow would be difficult to organize without the obvious help of my colleagues at PDF. But equally important is the help from everyone who will not be joining me in the room — you, the Parkinson’s Community. Your generous support of allows us to do what we do every day: support research and ideas that will improve the lives and futures of people touched by Parkinson’s. Our research program would simply not be without you. Thank you.

Understanding the FDA Committee’s Decision to Recommend Approval for Neurogenic Orthostatic Hypotension Drug

From James Beck, Ph.D., Director of Research Programs

You may have read the recent news about the small pharmaceutical company,Chelsea Therapeutics, and their drug Northera™ (droxidopa). Chelsea recently received the recommendation of a FDA advisory committee to approve droxidopa as a treatment for neurogenic orthostatic hypotension or NOH for short. This recommendation was a big surprise since FDA documents released ahead of the committee meeting showed that agency staff members were clearly against approval; nevertheless, this approval recommendation will strongly influence the final decision expected to be made later this month.


What is NOH?
Normally, blood pressure increases as you move from a lying down to a standing position. This increase is necessary in order to maintain adequate blood flow to the brain. Not enough blood (or the oxygen it carries) results in a host of unpleasant issues including light headedness, dizziness, fainting and falls. Your nervous system automatically senses when you stand and then causes this pressure change. For some, the neural response fails to work and they develop precipitously low blood pressure when they stand, hence the name neurogenic (neural origin) orthostatic (standing) hypotension (low blood pressure). There are reports that about 40 percent of people living with Parkinson’s disease have some degree of orthostatic hypotension that is almost always neurogenic in origin.


How might droxidopa treat NOH?
Just like levodopa is the precursor of dopamine for Parkinson’s disease, droxidopa is the precursor of the norepinephrine neurotransmitter for NOH. Norepinephrine is used by the peripheral nervous system to help regulate blood pressure, generally more norepinephrine leads to a higher blood pressure. These levels fluctuate as you move about your day. Therefore, the concept behind droxidopa is that the peripheral nerve cells that regulate blood pressure are able to convert droxidopa into norepinephrine and provide an increased blood pressure. Several studies done in people with multiple system atrophy and peripheral autonomic failure (two diseases that can lead to NOH) have shown promising results. Currently, Chelsea Therapeutics is also conducting a fairly large (200 participants) study of droxidopa in PD. Preliminary results from that have been encouraging as well.

The problem of current therapies
There is currently only one FDA approved drug, midodrine, that is used to treat orthostatic hypotension. Because of the rare nature of NOH, midodrine was approved as an orphan drug before large, key studies showing efficacy were performed. (Because orphan drugs are therapies that target rare diseases, they get special treatment from FDA.) However, for midodrine, those studies were not done as required. Now the FDA is pressuring the manufacturer of midodrine to do the studies or pull the drug off the market.


Why would the FDA be against droxidopa?
Even though droxidopa has shown evidence of helping with NOH, the clinical studies to demonstrate the efficacy of this drug are far from clear-cut. The issues are outlined in the FDA Advisory Committee materials. For instance, in one study, the droxidopa demonstrated a strong, initial increase in blood pressure, but the effect slowly declined over a period of weeks. The therapeutic effect only returned after people were told they were on the drug and advised to stay on it during an open label part of the trial. Despite the variable effect of droxidopa on blood pressure, participants in the study kept diaries that consistently indicated a benefit of the drug. Besides issues of efficacy, there are concerns that long-term use may cause problems because of drug toxicity and that contaminants in the manufacturing process may also be dangerous.



So why did the committee recommend droxidopa?
Others who observed the hearings have suggested that, ultimately, NOH is a serious unmet medical need worthy of its orphan drug status. Moreover, several people who are affected by NOH made compelling remarks that provided a human face and story to the effects of this condition. Even though those people were reimbursed by Chelsea for their travel, I think it helps demonstrate the importance of people living with a disease being able to speak up for their needs. And all the more reason that PDF is behind its Parkinson's Advocates in Research program to help empower people to do just that.

Droxidopa is still far from being approved, but I think the recent vote demonstrates the importance of having people living with a disease, whether it be NOH or Parkinson's, involved in all stages of the clinical research process to insure that their voice is heard.

What Can Alzheimer’s Tell us About Parkinson’s?

From James Beck, Ph.D., Director of Research Programs

Understanding how Parkinson’s disease starts and how it progresses remain two of the key unanswered questions about the disease. This is why a recent story in the New York Times caught my eye.

The article described how two independent groups of scientists found evidence that Alzheimer’s disease may spread from brain cell to brain cell much like a virus. These scientists engineered mice to make a human form of a protein called tau in only one small part of the brain. Clumps of the tau protein are a hallmark of Alzheimer’s disease. Like the rubble of demolished buildings, these clumps are all that are left of brains cells that have slowly died because of Alzheimer’s.

Proteins and Clumps

Proteins in the body are folded into special shapes … almost like pieces of origami. Some proteins, if they are not folded correctly to begin with or become “crumpled” due to some cellular problem, will stick together in clumps. Similar to how clumps of the protein tau are a hallmark of Alzheimer’s, clumps of a protein called alpha-synuclein are the hallmark by which Parkinson’s disease is diagnosed. These alpha-synuclein clumps are called Lewy bodies.

Parkinson’s and the Contagion Theory

Parkinson’s researchers have long noted what appears to be the spread of Lewy bodies from one brain region to another. Researchers observed possible clinical evidence that Parkinson’s could “spread” from one cell to another, when fetal cells were transplanted into the brains of people with Parkinson’s disease. The transplants subsequently developed Lewy bodies. That is, something about a Parkinson’s brain made genetically unrelated cells that were only a few years old develop the signs of Parkinson’s disease.

What came out of these observations was the controversial idea that Parkinson’s, once started, might be transmissible from brain cell to brain cell.

Several recent scientific papers are beginning to lend credence to this idea:

• Last year, Dr. Patrik Brundin’s research team in Lund, Sweden published a paper demonstrating that mis-folded alpha-synuclein (the basis of Lewy bodies) can spread from cell to cell in culture and could also spread in the brain of a mouse.
• More recently, Dr. Virginia Lee's team from the University of Pennsylvania published similar findings this past November.
• At a recent New York Academy of Sciences meeting on Parkinson’s disease, unpublished data was presented that also demonstrated how a single injection of alpha-synuclein clumps into a mouse brain could lead to the widespread formation of Lewy bodies in many different parts of the brain.

What Does It Mean?

Well it brings hope that a Parkinson’s therapy might be found in one of two ways: using special antibodies that target alpha-synuclein or a vaccine which primes the immune system to also target alpha-synuclein.

Either approach may not only halt the spread of Parkinson’s disease but maybe could also prevent it.

Your Feedback

What do you think about the recent Alzheimer’s study and how it relates to Parkinson’s? As always, please share your comments and I will do my best to respond.

Notes from AAN 2011, Part II: Which Doctors Treat Parkinson's?

From James Beck, Ph.D., Director of Research Programs

As mentioned last week, this year the American Academy of Neurology held its annual convention in Honolulu, Hawaii, attracting nearly 7,000 neurologists and neuroscientists.

I wanted to provide you with an update of interesting and new developments that were presented at the meeting last week, in particular, three studies which discussed whom people with living with Parkinson's disease see for their care.

#1-The first was a health economics presented by Marcy Tarrants, Ph.D., of Teva Neuroscience and her colleagues (presentation P01.087).

This group examined the records of newly-filled prescriptions for people diagnosed with Parkinson's and found that, overall:

• the prescribing doctor was a neurologist (both general and movement disorder specialists) in 46 percent of the cases;
• while the prescribing doctor was an internist or primary care physician in another 41 percent of cases.
  

However, when one examines whether those prescriptions are for new treatments (think newly diagnosed or just starting a medication) or for existing treatments (those who have been living with the disease), the numbers shifted:

• only 40 percent of the new treatment prescriptions were from neurologists;
• versus 59 percent of existing treatment prescriptions being made by neurologists.
  

#2- A similar study by Benjamin George, a medical student at the University of Rochester, and his colleagues who worked under the mentorship of Ray Dorsey, M.D., M.BA., now at Johns Hopkins University (presentation P01.088) found in a small study that:

• only 30 percent of those individuals with Parkinson's living in nursing homes see a neurologist;

• the rest see primary care physician or internist 50 percent of the time;

• and 20 percent see no physician at all.

#3-The results of the first two studies tie into the outcomes reported from a related report by Karen Zheng and colleagues working under the mentorship of Melissa Nirenberg, M.D., Ph.D., from the PDF Research Center at Weill Cornell Medical Center. (see photo; presentation P01.081). In a chart review of 120 people with Parkinson's, this group examined the underlying cause of those 25 percent who experienced acute worsening of their Parkinson's motor symptoms, or exacerbations. They found two main causes of exacerbations: infections and medication problems: about 25 percent suffered an infection, often a urinary tract infection, and 35 percent had problems with pharmacy errors or taking their medications on time (evenly split). While many of the exacerbations were reversible, about a third had recurrent problems and about a fifth never improved.



The lesson here is that prompt medical attention by someone trained to recognize the complications of Parkinson's by, you guessed it, a movement disorder specialist is important to achieving the best outcomes to these exacerbations.

Conclusions
These numbers in the first two studies, and the conclusions of the third, reiterate a concern that PDF has for PD community: not enough people are seeing the medical specialists who can best treat their disease.

PDF recommends everyone with PD see a movement disorder specialist or, if one is not in your area, a neurologist who can perhaps work with a specialist that you travel to see once or twice a year.

Do you need a recommendation? Call PDF to find the specialist nearest to you.

Please share your thoughts on these studies and check for further reports!

GMP Stem cells

A recent press release by the California Institute of Regenerative Medicine announced the award of $6 million to the lab of Xianmin Zeng, Ph.D., of the Buck Institute for Age Research and The City of Hope, a small biotech research/treatment center in Californina, to generate human stem cells that may one day be suitable for clinical treatment in Parkinson's. What Dr. Zeng's lab has accomplished - and now has funding to try on a large scale - is the ability to grow and differentiate stems cells using defined culture conditions - an important aspect of Good Manufacturing Practice (GMP) that the US Food and Drug Administration (FDA) requires for any compound that will be used for human therapeutics.

What does "defined" mean? It simply means that one knows exactly what compounds are added to the culture media -- the fluid used to grow and nuture cells. Typically, when scientists grow cells for research use, they use undefined conditions where they don't know exactly what the fluid contains. For example, if you are cooking something that requires a banana flavor, you could chose the defined route of just using banana flavoring in a bottle, which is a single chemical called isoamyl acetate. Alternatively, you could choose the undefined route and use a whole banana, which not only contains isoamyl acetate but a whole bunch of unknown chemicals and proteins.

Why does this matter? Replication and Safety.

• Replication: Because you don't know exactly what is contained in undefined media, it can be difficult to replicate. A classic example is from the early days of heart physiology. Many early advances in the field were made by Sydney Ringer. He created a defined media but used London tapwater as the source. He ran into difficulty trying to replicate his own experiments using distalled water. Turns out London tapwater has trace amounts of calcium which is essential for normal heart function...and he revised the formula for his now famous Ringer's saline solution.

• Safety: The safety issue centers around the fact that cells in culture often need various proteins and growth factors...not all of them are known. For research, the convenient answer is to use an undefined media, often this mean using an animal derived serum. Another approach has been to use what are called "feeder cells" which also provide the trace amounts of proteins and growth factors to keep stem cells alive. However, both approaches can expose stem cells to nasty foreign biologic material like viruses (both known and unknown) that could be devisatating if subsequently transplanted in to people.

So the advance Dr. Zeng's lab has made in creating GMP-compliant culture conditions is an important step in moving stem cells closer to use in human therapy.

WPC Science Day Two: Genetics Updates

From James Beck, Ph.D., Director of Research Programs

Here are some additional scientific updates from this week's 2nd World Parkinson Congress (WPC).

Michael Schlossmacher, M.D., reported the results of his recent experiments that demonstrate that mutations in the GBA gene, which were recently identified as a major risk factor for Parkinson's disease (PD), actually contribute to an increase in the levels of alpha-synuclein in nerve cells. Alpha-synuclein is the protein that accumulates in dying nerve cells and is the hallmark of Parkinson’s disease. This result provides a biological explanation as to the significance of these GBA mutations and their relevance to PD. That is to say, Dr. Schlossmacher has shown how mutations in the GBA gene are related to an increased risk of PD. His work has gone through peer review and is currently awaiting publication—we will let you know when it is published and report on his findings in more detail.

Additionally, Haydeh Payami, Ph.D., a research scientist from the Wadsworth Center and Director of the NeuroGenetics Research Consortium in New York State, reported late-breaking results of the re-analysis of a large-scale genetics study her team published this past March in Nature Genetics. The re-analysis examined whether there was a genetic interaction with the onset of Parkinson’s disease and the amount of coffee study participants consumed. Her team found a strong link with a particular gene called GRIN2A, which makes one component of the receptor protein that binds to an important neurotransmitter called glutamate. When this receptor protein binds too much glutamate, it becomes over-activated and can lead to cell death.

What is the role of coffee? Well, the caffeine in coffee indirectly alters how much glutamate is released from neurons by blocking the function of another receptor protein—the adenosine A2A receptor. This in turn, may prevent the cell death observed in the presence of too much glutamate. Indeed, epidemiological evidence suggests that coffee drinkers may have a lower risk of PD. However, Dr. Payami introduced a wrinkle in this concept. She suggests that her teams’s genetic data reveals that only some people may benefit from the strategy of blocking the A2A receptor. You see GRIN2A comes in two forms and only 25 percent of the population have the version which Dr. Payami suggests is beneficial.

Please keep in mind that Dr. Payami's study results were part of a late-breaking science presentation at the WPC, meaning the results were fresh from the lab and will need to be validated and reviewed by her peers. So as compelling as the results are, it will be interesting to see if these findings will stand after a critical examination has been performed. Whether her hypothesis regarding which form of GRIN2A is important is right or wrong, she raised an a critical issue that may be impact future drug discovery—the significance of genetically characterizing research participants. We are all genetically different, so is it so surprising that some people respond better to certain drugs than others? Maybe this is why many drugs fail clinical trials? What do you think?

As the science advances, you can count on PDF to keep you updated.

WPC Science Day Zero: Orthostatic Hypotension

From James Beck, Ph.D., Director of Research Programs

Yesterday, an industry-sponsored session for clinicians and scientists was held prior to the official start of 2nd World Parkinson Congress. Largely a review of current medical management of PD, the session included one tidbit that I found particularly interesting - a comment made by Mark Stacy, M.D.

He said that orthostatic hypotension, that is low blood pressure upon standing, is the most common, unrecognized symptom of PD.

Up to 40 percent of people with PD experience orthostatic hypotension. Drugs that are currently approved to treat hypotension, like midodrine, work, but may work too well. The problem for people with Parkinson's is that their blood pressure is generally normal upon lying down or sitting, and problematic only when standing. But midodrine is not “smart” enough to figure this out. So while the drug fixes the problem of low blood pressure when a person is standing up, it also acts when a person is not standing, often causing the problem of hypertension, i.e., high blood pressure.

A solution may be in the works in the form of a drug called droxipoda, approved in Japan and under clinical development in the US by Chelsea Therapeutics (one of the industry sponsors of the session). Much like levodopa, or L-DOPA, a dopamine precursor given to replace dopamine, droxidopa or L-DOPS, is a precursor to the neurotransmitter norepinephrine and is given as its replacement. Preliminary evidence from clinical trials, presented by Phillip Low, M.D. from the Mayo Clinic in Rochester, MN, seems to indicate that droxidopa may benefit orthostatic hypotension in PD without causing hypertension when a person is not standing.

It will be interesting to follow the fate of this drug as it is tested. Do you agree orthostatic hypotension is a problem? Are you waiting for better treatment for it? Let us know in the comment section below.

Sham Surgery

In clinical trials that test new drugs for Parkinson’s disease, the process is fairly straightforward: some people get the real stuff and others get a sugar or placebo pill. It looks identical to the pill containing the new drug, but doesn’t offer the new compound. Here everyone (the person with Parkinson’s and physician) enters the trial knowing that a certain amount of deception is necessary from the outset….no one knows which pill is which. That is a good thing scientifically.

There is an overwhelming consensus that double-blinded experiments, in which participants are randomly assigned to receive a placebo, result in the strongest and most reliable evidence – which means they give us the best indicator of which experimental treatments would truly help people living with PD and, just as importantly, help shield people from treatments that don’t.

This scenario gets more complicated when the new “drug” is actually a surgical intervention, in the case of PD, brain surgery. What is the surgical equivalent of a sugar pill? It’s called sham surgery and it’s not simple.

So the National Institutes of Health (NIH) held a two day conference, part of which is now available to view online via videocast, to discuss the scientific and ethical considerations underlying sham surgery for neurodegenerative diseases, chiefly Parkinson’s disease.

Why Sham Surgery?

Essentially, a clinical trial is an experiment where the results are unknown. Sure, previous data or testing indicates it is worth spending loads of money on it; but, really, no one knows how the experiment or trial will end...at least that is how it is supposed to work. But because clinical trials are experiments involving humans, the process can quickly be biased by what people think or are expecting to happen: people with Parkinson’s believe they may be getting better and their physicians may too easily agree. Enter the very powerful and very real placebo effect in PD (see here and here for two studies highlighted by panelist Jon Stoessl, M.D.).

So if you have PD and the placebo effect can help you feel better, what is the big deal? Why not spend all this energy making the placebo effect better? The problem is the placebo effect works by convincing the individual something is real when it is in fact not. Before science entered medicine, placebo was mostly the only game in town. So while studying the mechanism underlying the placebo effect is a worthy vein of research, the placebo effect remains no substitute for medical therapy.

A solution has been to control for the placebo effect by keeping everyone in the dark (also called blinding or masking) about who is getting the experimental treatment and who is not. This way, designers of clinical trials try to eliminate the obvious forms of bias, like the placebo effect, as well as not so obvious forms of bias that are harder to predict.

Many PD therapeutics, however, start out as open-label trials where no secrets are kept and everyone knows who is getting the experimental treatment. It may not be surprising, as noted by meeting panelist Steven Piantadosi M.D., Ph.D., that these early trials often end in success —frequently demonstrating a 30 percent improvement in PD symptoms — yet are later thrown upon the bin heap of failure once the more rigorous experiment is conducted. With so many successes followed by failures, what is the price to the person with Parkinson’s?

Looking Ahead
There is no easy answer to this multi-faceted problem. However, several ideas emerged from the discussion at last month’s meeting.

1. Be more rigorous in the preclinical stage. Without a true model of PD in animals, investigators need to be more thorough in understanding the biology behind a treatment before trying it in humans. (Mice are not people.)
2. Early trials should be large enough to detect potential adverse events and should include some form of blinding to make them most informative about future directions.
3. Sham controls should minimize the risk to the participant by using minimally invasive procedures.
4. If the results of an open-label study are used to decide whether to go forward with more testing the treatment effect should be very large.
   

These are just a few of the suggestions that emerged to minimize the use of sham surgery while maximizing its scientific potential when employed. As the draft recommendations are refined by the panel participants, they will be available for public comment. We will let you know when that happens, so be certain to check back.

What Do You Think?

So what are your thoughts on how clinical trials are designed and conducted? When would it be appropriate to use sham surgery?

A Tale of Two Research Strategies

From James Beck, Ph.D., Director of Research Programs

I hope you saw the news item PDF posted last week in which we announced $1.2 million in funding from two of PDF’s investigator-initiated grants programs for 13 Parkinson's research projects.

I want to share with you the approaches behind these two programs – both because they are philosophies of which I am particularly proud and more importantly, because we at PDF think these philosophies may also yield “the next great idea” for PD.

First among these approaches is PDF's goal to fund grassroots research, which we do through our International Research Grants Program, or IRGP. Here, PDF puts out a call for proposals that are rooted in the creativity of individual scientists — folks who are experts in their field with first-hand knowledge of the science of PD. The creativity of these scientists is brought to bear to tackle a set of problems on the path to a cure. Each scientist formulates his/her ideas into testable hypotheses and the merits of those ideas are then judged by an independent panel of PD researchers convened by PDF. PDF then extends support - up to the limit of available resources made possible by our donors - to the best ideas in our effort to affect a cure and help those living with the disease.

This approach to finding and funding the best science is certainly not new, though in the business world it is akin to the very popular method of “crowdsourcing” ideas...where new ideas are not generated by an organization, but by a community. In the world of PD, this approach of supporting ideas from individuals has led to the biggest advances in managing PD – levodopa and DBS.

Thus, PDF aims – by leveraging its initial research investment into supporting great ideas generated by the “crowd” of scientists – to help bring about the next big thing in PD.

Another related approach to research employed by PDF is to invest in talented young researchers. As the first not-for-profit organization created to focus on PD, PDF has an established commitment to fighting PD. Because the battle has yet to be won, we absolutely must invest in the future to ensure PD’s defeat. So, through our Fellowship Program, we are working to make certain that the best and brightest young talent joins and continues the fight. In this program, PDF funds young investigators to support them at a critical juncture in their scientific training – whether it be basic science or clinical research.

Since PDF’s grants are awarded exclusively on scientific merit, it is amazing to see how many young investigators were able to generate ideas that successfully competed in this year’s grant competition. Less than half (66) of the 150 total scientists who applied were young scientists fresh from their doctorates…yet, of the eight grants awarded this year, six went to support the Fellows in this category. This is quite an achievement. It provides great promise for the future of Parkinson’s research.

For more information on projects we’re funding, browse this year’s abstracts. We look forward to reporting on the results of this research and the impact we hope it makes upon science and our understanding and treatment of PD. Stay tuned.

Notes from AAN 2010: Part II

From James Beck Ph.D., Director of Research Programs

As promised on Friday, here’s an additional update from last month’s American Academy of Neurology (AAN) annual meeting.

In addition to the study mentioned above, another interesting one - presented by Nasim R. Khadem and Melissa J. Nirenberg, M.D., Ph.D. – investigated the rates of pharmacy errors in Parkinson’s medications.

In this small, prospective study of 73 individuals, the investigators found that about ten percent of people with Parkinson's had the incorrect Parkinson's medication dispensed to them during a one-year period. Dr. Nirenberg alluded to this problem in her recent PD ExpertBriefing (and subsequent newsletter article (see page 4), but this is the first example of data to demonstrate the precise rate of these errors for people living with PD.

Of the other findings this study highlighted, two were noteworthy:

• 50 percent of the prescriptions were made using computerized physician order entry system


• Those individuals who noticed the change in their medication and questioned it still received the wrong information from their pharmacy
  

Since the effects of an incorrect dosage can be very debilitating, this study just emphasizes the need to be ever vigilant when you get your prescriptions refilled.

Have you had problems at the pharmacy? Please let us know about your experiences.

Notes from AAN 2010: Part I

From James Beck Ph.D., Director of Research Programs

Sorry for the delay in postings. As you will see in the next several posts, I have been a bit busy attending scientific meetings that have a direct impact upon Parkinson's.

The American Academy of Neurology annual meeting was held recently in Toronto. This a large international meeting where neurologists come together to learn and share new scientific progress (largely clinical) related to diseases of the nervous system. I already covered some of the new findings related to imaging and PD in my interview with David Eidelberg, M.D.,, but I wanted to share a couple of other brief things that you might find relevant, the first of which I'll include below. Look for another update next week.

A troubling non-motor feature of PD is psychosis, which is often experienced in the form of hallucinations. Yet, treatments for it have been limited. One drug that is in development for this is pimavanserin. At the AAN meeting, the results of a Phase III trial using this drug were reported by Joseph Friedman, M.D., of Brown University. Though the drug was well-tolerated, the outcome of this safety and efficacy study were negative (a rarity to find negative results reported at all). The trial missed its primary endpoint on reduced psychosis—that is the drug worked no better than the placebo.

What was interesting is that Dr. Friedman suggested that the trial failure may have been due to a greater than expected placebo effect, meaning people taking a sugar pill reported a similar reduction in symptoms as those taking the experimental medication. (Not so unusual for therapies treating motor symptoms in PD, but less common here.) In particular, non-North American study sites (i.e., Eastern Europe and India in particular) reported a much greater placebo effect than North American study sites. It is likely the results from those sites altered the final results while just using data from the North American sites suggested a more positive outcome of the drug.

Apparently, there were differences in how clinicians interacted with their patients and this attests to the difficulty in international clinical trials for some diseases. Nevertheless, Dr. Friedman indicated that the company behind the drug, Acadia Pharmaceuticals, is still pursuing the drug candidate with a revised Phase III study. It will be interesting to see whether the new Phase III trial to be conducted in North America only will end with different, more positive results.

For those interested in Dr. Friedman's work, he recently presented a one-hour PD ExpertBriefing with PDF on a different topic. View this seminar, entitled Fatigue, Sleep Disorders and Parkinson's Disease, on the PDF website.

Also, check back on Monday for news about pharmacy errors in Parkinson's.

Interview with Dr. Eidelberg at AAN

From James Beck Ph.D., Director of Research Programs

At the American Academy of Neurology (AAN) annual meeting in Toronto, I had the opportunity to sit down and chat with David Eidelberg, M.D., this year’s PDF-AAN Movement Disorder Research Awardee. Dr. Eidelberg is a Professor of Neurology at New York University School of Medicine and Director of both the Center of Neurosciences at the Feinstein Institute for Medical Research and of the Movement Disorders and Functional Neuroimaging Center at North Shore Long Island Jewish Health Systems. He has been hailed as an innovative thinker who has developed new ideas to advance our understanding of Parkinson’s disease (PD) and movement disorders in general.

In particular, Dr. Eidelberg (pictured at right) is known for his work with neuroimaging. In a recent study, he and his colleagues used one neuroimaging method – FDG-PET scans—combined with their own computerized image classification program to accurately differentiate people living with classic Parkinson’s from those living with related disorders, or parkinsonisms, such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA).

How does this work and is it a real option for solving cases of difficult diagnosis? Is the cost prohibitive? As we find out below, the technique may not be ready for maintstream use, but it is helpful in teaching us more about Parkinson’s.


Q1: Your team's recently published study in Lancet Neurology, the culmination of many years of work, used a special form of glucose to measure brain metabolism via a type of imaging called FDG-PET in order to differentiate PD from other related disorders like PSP and MSA. Can you briefly explain how FDG-PET works and discuss your method of classifying classic Parkinson’s versus PSP and MSA?


A: The name “FDG-PET” simply refers to the two parts that comprise the imaging process—a tracer (FDG) and an imager (PET). For the first part, FDG, it is important to understand that the living brain, even at rest, consumes glucose (sugar) as its energy source. In our study, we took advantage of this fact by ‘tagging’ glucose with a harmless, FDA-approved radioactive molecule to see what parts of the brain were more active than others. The resulting compound is called 18F-fluorodeoxyglucose or FDG for short. Part two, PET, simply refers to the specialized imaging apparatus, or positron emission tomography machine, that is used to measure the location of the FDG as it gets utilized in the brain. By studying the images we take, we can then observe how metabolically active are the various regions of person’s brain.

Administering the FDG is very straightforward. The person undergoing imaging is injected with a small amount of FDG through an IV line and then is able to move around freely for about 25 minutes while the compound circulates in his or her body. The PET scan itself is also relatively brief and lasts about 20 minutes. Results are ready within a few minutes of completing the scan.

If the scan shows high FDG uptake in a particular brain region, this reflects tissue with high metabolic activity, whereas low FDG uptake reflects tissue with low metabolic demand, due to loss of synaptic activity (loss of input signals from other brain regions, compromised cell function, or even neuronal death).

We have found that the brains of people living with neurodegenerative diseases, including idiopathic Parkinson’s disease and atypical parkinsonian syndromes such as MSA and PSP, are associated with distinct patterns of altered regional metabolism that are indicators of highly specific pathological change. We can observe the activity of each of these abnormal patterns of brain metabolism in an individual’s FDG PET to measure his or her disease severity. This is important, because in clinical practice, people who actually have MSA and PSP can be misdiagnosed as having PD, particularly early in the clinical course.

While the interpretation of the results of a FDG-PET scan can currently be made by someone who is highly trained to read these studies, the problem is that there are more of these machines available than are physicians trained to interpret the results. Therefore, in our recent study, we developed a fully automated computer algorithm to differentiate accurately between PD, MSA and PSP. In addition, this approach allows for computing the probabilities of each of the three disorders in a given parkinsonian individual based on the expression of the disease patterns in his or her brain.

By comparing the disease probabilities in each case with the imaging criteria for each disease possibility, the person could then be given a tentative pattern-based diagnosis. This automated approach remains experimental and we intend to be able to test and validate it in a larger, multi-center study before it would be widely available for use.

Q2: How do the sensitivity and specificity and predictive rates of your method compare to a clinician’s diagnosis of PD, or even diagnostic approaches for other diseases?

A: In the population of people with Parkinson’s that we studied, the image-based diagnoses are both sensitive and specific – meaning very accurate – when compared to the final clinical diagnoses obtained by movement disorders specialists who followed the same individuals for several years. Our imaging approach was designed as a confirmatory diagnostic test to assist clinicians in specialty practices.

We therefore focused on something called the positive predictive value (PPV), a measure of the accuracy of classification using the early scan versus the later clinical ascertainment by a movement disorder specialist. Indeed, our automated classification approach achieved a PPV of 98% for diagnosing PD, 97% for MSA, and 91% for PSP. More importantly, the diagnostic accuracy of our approach remained excellent (> 90%) even in people in the early stages of parkinsonism with very short symptom durations (i.e., >94%) of the technique. We note that our approach also had reasonable sensitivity (~85%), which is a little lower than seen with dopamine imaging methods like FDOPA PET and βCIT-SPECT. It is important to appreciate that the latter imaging methods are often used as screening tools to distinguish people with presynaptic nigrostriatal defects from healthy subjects –with very few false negatives. These methods, however, have limited specificity in that they don’t do a good job in separating PD from atypical look-a-like conditions, because both have presynaptic nigrostriatal dopamine abnormalities.

Q3: Given the cost of this imaging to people with Parkinson's (and parkinsonisms) and insurance companies, do you think it will be practical to use such techniques beyond academic medicine, e.g., would imaging techniques such FDG-SPECT or BOLD-MRI offer viable approaches too?


A: Our study demonstrated that our approach is most useful to assist in differential diagnosis of individuals with uncertain parkinsonism. Previous research has shown that such individuals are not infrequently misdiagnosed (~25%), especially at early stages. Indeed, such diagnostic errors can be costly because of the expense and morbidity (complications) of attendant management decisions, as can happen when people with atypical parkinsonian syndromes are referred for invasive procedures such as DBS. By the same token, incorrect early diagnosis can lead to problems in the conduct and interpretation of clinical trials of potential disease modifying agents. So when applied correctly, this technique could help lower the costs of incorrect treatments for some people.

Regarding the costs of FDG-PET, it is important to bear in mind that this FDA-approved imaging modality is now widely available (most Americans live within 70 miles of a clinical PET instrument) and is routinely reimbursed for other neurological indications including epilepsy, brain tumor and dementia. Moreover, the costs (and invasiveness) of this procedure have declined steadily over the past five years and is now in the range of $1500-2000.

Lastly, it is important to realize that pattern-based diagnostic algorithms such as ours do not specifically require FDG-PET. Indeed, we and others have shown recently how this method can be easily applied to other imaging techniques, i.e., perfusion imaging of the brain with SPECT and with functional MRI. While FDG-PET is currently the clinical “gold standard” for resting state metabolic imaging, it is likely that these (and similar) techniques will ultimately be used for pattern-based diagnosis on a broader clinical scale.


Q4) There seems to be a real push, as evidenced in the abstracts presented here at AAN in Toronto, to identify potential anatomic differences (volumetric magnetic resonance imaging (MRI) or diffusion trace imaging (DTI)) in the brains of people living with Parkinson's. Where do you feel that technology stands and what promise do you think it holds for the future?

A: While these new anatomical approaches can be used to identify significant brain abnormalities, it is not clear how “diagnostic” they will prove to be on the individual subject level. Progressive changes in local tissue volume (voxel-based morphometry, VBM) or pathway microstructure (DTI) occur in PD as a reflection of ongoing neurodegeneration. But how large are these regional changes at early stages of disease, and how quickly do they evolve over time? Also, it is important to understand how these structural abnormalities relate to changes in brain function – both regionally and at the circuit level. Indeed, such changes can be extensive and are likely to be present before symptoms actually appear (see our recent paper mentioned above). In the end, complementary approaches employing specialized MRI scans to elucidate brain structure and anatomy, in conjunction with neurochemistry/metabolism imaging to reveal brain function, may provide the most effective strategy to identify robust imaging biomarkers for Parkinson’s.


PDF thanks Dr. Eidelberg for his time. Do you have questions or thoughts on his research? Please post your comments and we'll try to answer them to the best of our ability.

Watch for Next Tuesday's Interview with Dr. Eidelberg

From James Beck, Ph.D., Director of Research Programs

Do you have questions about brain imaging and its potential for diagnosing and measuring Parkinson's? Submit your questions now to PDF and we'll bring them directly to the experts. Next week, I'll be interviewing David Eidelberg, M.D., during the Annual Meeting of the American Association of Neurology (AAN) in Toronto, Canada, a major event that brings together neurologists from all over world.

During the AAN meeting, Dr. Eidelberg will become the tenth recipient of the PDF-endowed Movement Disorders Research Award. He is being recognized for his work in brain imaging and Parkinson's. His team's recently published report in The Lancet Neurology described an automated process to classify the images from a type of brain scan called a fluoro-deoxy-glucose (FDG) positron emission tomography. This method could help separate Parkinson's disease from other related diseases, or parkinsonisms, possibly leading to an ultimate diagnosis years earlier than before.

Submit a question by Monday, April 11 and I'll bring it with me (Dr. Eidelberg isn't available for general PD questions, but you can submit those questions to our Parkinson's Information Service at http://www.pdf.org/en/pins_question)

The full interview will be posted on this blog by 5 PM ET, Thursday April 15.

Submit a Question

Who Has Parkinson's?

From James Beck Ph.D., Director of Research Programs

When battling a disease of unknown origin, like Parkinson’s disease (PD), knowledge is power. Knowing something even as simple as the number of people living with the disease, or its prevalence, is very important. With Parkinson’s, knowledge of prevalence and incidence can help not only to appropriately advocate for scarce healthcare resources and research dollars but, when tied with other information like location, age, and gender, it can also shed light onto possible causes of the disease itself, e.g., environmental factors.

However, determining the prevalence of PD is not simple. While some other diseases are counted through a national registry, there isn’t yet one for Parkinson’s. (More on that later). Without a registry, the recognized gold standard method for assessing the number of people living with Parkinson’s is the door-to-door survey. This is an arduous process and the most recent survey conducted in the US occurred in 1978 and was published in 1985. It took place in the rural county of Copiah, Mississippi (population 23,842). This frequently cited survey has been used by some to estimate the number of people living with PD in the US - an estimate which stood at 340,000 in 2005 for people over the age of 50. Since this estimate neither includes people under the age of 50, nor those who have not yet been diagnosed, PDF and other organizations estimate a higher prevalence for Parkinson's. For instance, PDF estimates that there are nearly one million people in the US living with Parkinson's.

It makes one wonder…how accurately can data from a small rural county in the South be applied to the rest of the geographically diverse US? Well, a recent study has measured a more diverse group, leveraging the extremely large US Medicare database. This database includes medical information about 98 percent of the population age 65 or older, i.e., greater than 29 million people. This study has found different results:

• The prevalence of PD for those 65 and older is 1.6 percent (vs. 0.75 percent as reported in the 1985 study), meaning there are actually an estimated 483,000 people living with PD who are 65 and older vs. the 276,000 estimated using the earlier Copiah data for the same age group.
  


• The prevalence of Parkinson’s shows a racial distribution with about 1.5 times the level observed in whites than in blacks and Asians, though Hispanics had nearly the same prevalence as whites.
  


• There is a geographic distribution, or a ‘PD Belt’ as the authors describe it, of both the numbers living with and diagnosed with Parkinson’s. The highest levels of Parkinson’s are found in the northern Midwest and Northeast.
  


• Along these same lines, there is a higher prevalence and incidence of Parkinson's in urban environments vs. rural environments.
  


• Interestingly, the Medicare data for Copiah County demonstrated one of the lowest rates of prevalence -- about 1.1 percent -- not too far off the 1985 mark.
  

Are These Numbers Correct?

The results of this study are not perfect. One issue is that the study relied entirely upon diagnosis codes, which were not validated with spot checks. Diagnoses are recorded on a person’s medical records, and thus can be helpful in assessing who has Parkinson’s. But there is room for error. One study shows that even Parkinson’s experts who see hundreds of people with PD a year are only right in their diagnoses 90 percent of the time, so it is likely community-based physicians who only see 3-4 cases a year may have erred too.

Still, the results from this study provide a newly revised estimate of the number of people living with PD in the US…more inline with the anecdotal evidence that we at PDF hear from people living with PD. The PD Belt that researchers report is also interesting because the areas with the highest incidence and prevalence are also areas with the highest pesticide use and pollution levels—environmental factors hypothesized to play a role in PD. With so little understanding as to the cause of idiopathic PD, perhaps this information will guide future epidemiological research.

Although compelling, the PD community is still left with imperfect information about the nature of this disease. One possible solution would be the formation of a national registry for PD. A bill for creating exactly that is before both houses of Congress. I encourage everyone to get involved and help see this bill passed so that we can get the information we need about this disease.