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News in Brief

Genetic Link Found Between PD and Gaucher’s Disease

People who are carriers of the genetic mutation in a gene known as GBA have at least five times the normal risk of developing Parkinson’s disease (PD), according to a report in the October 22, 2009, issue of the New England Journal of Medicine.  Mutations in the same gene, which provides instructions for producing the enzyme glucocerebrosidase, have been shown to cause the rare disorder known as Gaucher’s disease.

Clinicians had long noticed an association between Gaucher’s disease and PD.  In rare cases, people with Gaucher’s disease developed PD-like symptoms; more recently, scientists noted that relatives of people with Gaucher’s disease had an increased incidence of PD.

Gaucher’s disease develops when both copies of the GBA gene are mutated.  Normally a person has two working copies of the gene.  A mutation in one copy of the gene causes no symptoms and was long thought to be harmless.

These and other observed links between the diseases prompted lead investigator Ellen Sidransky, M.D., of the National Human Genome Research Institute to study how frequently people with PD carry the genetic mutations known to cause Gaucher’s disease.  Dr. Sidransky organized a consortium of 64 researchers at 16 institutions around the world, who were already analyzing the genetics of people with PD.  In total, the study involved about 10,000 people.

The researchers focused on studying two common variants of the GBA gene, from among the nearly 300 mutations identified by scientists (and carried by about one in 100 Americans).  In an ethnically diverse group of 5,691 people with PD, they found that 3.2 percent of the group had at least one of these variants, compared to 0.6 percent in a similar group of healthy people.  Since mutations in the GBA gene are more common among Ashkenazi Jews (one in 15 people is a carrier), researchers studied this sub-group and found the incidence of one or more of these variants was 15.3 percent in people with PD and 3.4 percent in healthy people. 

Since these tests only focused on two common GBA mutations, the scientists also examined the full gene in 2,000 non-Ashkenazi individuals living with Parkinson’s.  They found that nearly seven percent of people with PD had a GBA gene mutation. Still, this limited test missed nearly half of the mutations possible in GBA. 

Overall, people with Parkinson’s are 5.43 times more likely to carry a GBA mutation than individuals without PD.  These findings indicate that being a carrier – having one mutated copy of a GBA gene – increases a person’s risk of developing PD over five-fold.  The researchers also found that people with PD who had mutations in GBA tended to have been diagnosed at a younger age and have a family history of PD, a lower incidence of bradykinesia (slow movement) and resting tremor, and a higher incidence of cognitive changes.

This makes the newly identified genetic risk factor, among the dozen known to scientists, the most common one found for PD to date.  Mutations in the GBA gene most likely increase susceptibility to PD, which combined with other factors, results in disease.  The mechanisms by which this happens are not understood and require further research.

This study was conducted with funding from PDF, as part of the Columbia University Center Grant. Columbia was one of the 16 centers that participated in the study.

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Uric Acid and the Progression of Parkinson’s Disease

Uric acid, the chemical that causes gout and kidney stones, may be a marker for the progression of Parkinson’s disease (PD), according to a recent study published in the October 12 online edition of Archives of Neurology.

Investigators led by Alberto Ascherio, M.D., Dr.P.H., and Michael Schwarzschild, M.D., Ph.D., at Harvard University recently analyzed samples of blood and cerebrospinal fluid (the body fluid that bathes the brain) that had been collected from nearly 800 people with early-stage PD in the 1980s as part of another clinical trial. 

While all of the individuals with PD showed normal levels of uric acid in their blood, when researchers looked at the group more closely, an interesting statistical relationship between uric acid and PD progression seemed apparent.  Scientists observed that people with Parkinson’s who had the high-normal levels of uric acid had a slightly reduced risk of needing to take levodopa for their PD than those individuals with lower uric acid levels.  This indicated a statistical trend in people in the high end of the normal range for uric acid, towards slower PD progression.

The relationship between uric acid and PD progression is not yet fully understood.  Many researchers believe that oxidation plays a role in PD, and uric acid participates in oxidation reactions.  Researchers suspect that uric acid could be a specific marker of PD, but this hypothesis needs further exploration.  A clinical trial is now under way to test the safety of the dietary supplement inosine, which the body converts into urate.  To learn more about this trial, visit www.PDtrials.org

It is emphasized the uric acid levels in this study were all within the normal range.  Researchers caution that raising the uric levels in the body by supplements or diet could result in gout, kidney stones, as well as hypertension and heart disease. 

This study was conducted with funding from PDF, as part of the Advancing Parkinson’s Treatments (APT) Innovations Grant, which funds innovative programs that facilitate the movement of treatments from “bench to bedside.”

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Study of Medication’s Ability to Slow PD Progression Shows Mixed Results

Azilect®, a medication already approved and on the market for symptomatic relief of Parkinson’s disease (PD), showed mixed results in a study investigating its potential for protecting the brain cells that die in Parkinson’s.  The report appeared in the New England Journal of Medicine on September 24, 2009. 

Lead investigator C. Warren Olanow, M.D., and his colleagues conducted a multi-center study known as ADAGIO (Attenuation of Disease Progression with Azilect Given Once Daily) to examine the effects of rasagiline (Azilect) on the progression of clinical signs of Parkinson’s.  The study was sponsored by Teva Pharmaceuticals, the manufacturer of Azilect.

Since the beginning of large-scale clinical trials for Parkinson’s, researchers have attempted to distinguish between these two aims: (i) does the drug reduce the symptoms of PD?; and (ii) does the drug slow the progression of PD?  To date, no study design has successfully proven that a drug that reduces the symptoms also provides a neuroprotective effect.

This study attempted to investigate whether rasagiline is neuroprotective for people with PD by using a “delayed-start” treatment design.  The researchers looked at over 950 people living with Parkinson’s, and studied the effects of two doses of rasagiline, one-milligram (mg.) and two-mg. daily.  Within each dosage group, one group of people with Parkinson’s got a nine-month head start in treatment, while the other group received treatment that was delayed by nine months.  Researchers followed up with all participants throughout the study to track the progression of their PD symptoms, using the Unified Parkinson’s Disease Rating Scale.  Assuming that the drug reduced the symptoms of PD (e.g., tremor, rigidity, slowness) by an equal amount in each group, any differences in outcome would be assumed to come from the delayed start, and suggest the possibility of neuroprotection.

Unfortunately, the study gave a conflicting result: those participants who received a daily one-mg. dose of rasagiline had a superior outcome when the drug was started nine months earlier.  This supports the idea that the drug may have an effect on disease progression.  By contrast, those receiving a daily dose twice as large, two-mg., did not show this benefit, which does not support the claim of neuroprotection.  In the end, the researchers of this study concluded that the effect of neuroprotection remains unproven, and that more study is needed.

“The results have been fairly reported with appropriate caution on interpretation,” says Christopher Goetz, M.D., Director of the PDF Parkinson’s Disease Research Center at Rush University Medical Center in Chicago.  “Clearly, if one focuses on the results with the one-mg. dose, we would want to recommend early intervention as opposed to holding off on treatment to reserve it for later.  If one focuses on the results with the two-mg. results, we would not have any reason to promote early treatment, since the outcomes achieved with the extra duration of treatment did not meet the outcome measures predicted. More research is needed and a longer follow-up on these patients since PD lasts far longer than 18 months.”

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For the latest in Parkison's science news, visit PDF's Science News page.