Screen uses ‘metabolomic profile’ to spot disease-linked changes, Weill Cornell team reports

From Eurekalert.org

A test that profiles molecular biomarkers in blood could become the first accurate diagnostic test for Parkinson’s disease, new research shows.

The screen relies on changes in dozens of small molecules in serum. These “metabolomic” alterations form a unique pattern in people with Parkinson’s disease, according to a team led by researchers at the Weill Cornell Medical College in New York City.

They published the findings in the journal Brain.

“A reliable blood test for Parkinson’s disease would revolutionize not only the care of people with this debilitating illness, it would facilitate research as well,” notes study senior author Dr. M. Flint Beal, chairman and Anne Parrish Titzell Professor of Neurology at Weill Cornell Medical College, and neurologist-in-chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

According to the National Parkinson Foundation, an estimated 1.5 million Americans have the neurodegenerative disease, and 60,000 new cases are diagnosed each year. Actor Michael J. Fox, boxer Muhammad Ali, and former U.S. Attorney General Janet Reno all suffer from Parkinson’s, which strikes men and women in roughly equal numbers.

“Right now, a Parkinson’s diagnosis is made solely on a clinical review of symptoms — we have no biologic test,” notes Dr. Beal. At best, a symptom-based screen is still only 90 percent accurate, he adds.

“That can cause real problems, because that remaining 10 percent of patients — who may have look-alike conditions such as multi-system atrophy or progressive supranuclear palsy — end up getting treated with Parkinson’s drugs,” Dr. Beal says. “These medicines may appear to help them a little while, but in the meantime, they haven’t been getting the treatment that’s necessarily best for them.”

An early-detection test would also be enormously useful in tracking the health of patients who may be at higher risk for Parkinson’s, such as those with a family history of the disease.

Finally, the integrity of clinical trials is undermined by the lack of an accurate screen, Dr. Beal notes. “Every time you do a clinical trial into Parkinson’s and you have patients that are misdiagnosed, it enters ‘noise’ into the analysis, skewing the results. A truly reliable test could help eliminate that,” the researcher notes.

That’s why encouraging results for the new test — based on a patient’s “metabolomic profile” — are so important.

Metabolomics is the study of changes in thousands of distinct, very small molecules found in body fluids or tissues. “Anytime you have a genetic or environmental perturbation, these molecules are altered in specific ways,” Dr. Beal explains.

Because Parkinson’s treatment could itself trigger some of these alterations, the researchers first compared metabolomic patterns in the blood of Parkinson’s patients who were not undergoing treatment versus those who were medicated. “That gave us a ‘medication-free’ profile that we could use going forward,” Dr. Beal explains.

In the next stage of the research, the team compared blood samples from 66 patients with Parkinson’s disease against 25 healthy controls (most of whom were the patients’ spouses). The metabolomic analysis included over 2,000 small molecules found in the blood.

“We discovered a clear differentiation between the metabolomic profiles of the Parkinson’s disease patients versus those of the controls,” Dr. Beal says. “No one molecule was definitive, but a pattern of about 160 compounds emerged that was highly specific to Parkinson’s patients.”

The significance of many individual compounds to the disease remains unknown and will be the focus of future study. But changes in a few well-known metabolites linked to oxidative stress were clearly linked to Parkinson’s. These included low levels of the antioxidant uric acid; an increase in blood levels of another antioxidant, glutathione; and increased levels of a marker for oxidative damage called 8-OHdG.

“Together, these and other compounds were arranged into a metabolomic pattern that identified Parkinson’s disease with great accuracy,” Dr. Beal says.

He stressed that more work needs to be done to validate the finding, and a test that might be used routinely by doctors is still a few years away.

“We are currently enlarging the sample size and studying people at serial intervals, to see if this test might also serve as a benchmark for disease progression,” Dr. Beal says. “We are also looking at people who carry a gene for a familial form of Parkinson’s, but who do not have the illness now. We hope to track them over time to see if this metabolomic profile is predictive of disease onset.”

If those data prove as promising as this early trial, an early-detection blood test for Parkinson’s disease could someday become a reality. According to Dr. Beal, “That would be a big step forward for both the treatment and the study of this devastating illness.”

This work was supported by the Michael J. Fox Foundation, the Department of Defense, and Edwin and Carolyne Levy.

Co-researchers include lead researcher Dr. Mikhail Bogdanov, of Weill Cornell Medical College and Bedford VA Medical Center, Bedford, Mass.; Dr. Wayne R. Matson, of Bedford VA Medical Center; Dr. Lei Wang, of Weill Cornell and Bedford VA Medical Center; and Dr. Rachel Saunders-Pullman and Dr. Susan S. Bressman, of Albert Einstein College of Medicine, New York City.

From NaturalNews.com

A class action by a law firm in Melbourne (Australia) is about to be taken against two pharmaceutical companies that produce drugs for treating Parkinson’s disease. The action is being taken due to side effects caused by the drugs and the lack of warnings given to doctors and their patients about these side effects.

Parkinson’s disease results from an imbalance of dopamine which regulates movement. Parkinson’s can effect people differently but typical symptoms include trembling or shaking, muscle stiffness and slow body movements.

The Parkinson’s drugs at issue are of a class of drugs known as dopamine agonists. These agonists restore the imbalance of dopamine in the brain. And while they also stimulate the reward centre in the brain, they can overstimulate leading to compulsive behaviours according to neurologist Dr. Andrew Evans (see the abc link below).

These behaviours include compulsive gambling and shopping as well as heightened sexual urges, and have lead to serious problems. The compulsive behaviours stopped when patients’ stopped taking the drugs.

One of the drugs, called cabergoline, is marketed in Australia as Cabaser and is produced by Pfizer. The other is pergolide marketed as Permax by Valeant Pharmaceuticals. Generic versions of pergolide may also be manufactured by Par and Teva.

In March 2007 the FDA announced that Permax was being voluntarily withdrawn from sale because of “risks of serious damage to patients’ heart valves” ((http://www.fda.gov/bbs/topics/NEWS/2007…) . This is not mentioned in the news releases on Valeant’s website, see ((http://www.valeant.com/mediaCenter/news…) .

There are two crucial issues. One is that for both drugs, information about compulsive behaviours was not available for doctors (until 2006 and 2007 for Cabaser) nor is advice given in Consumer Medical Information.

Secondly, the drug companies would have known about the side effects from around 2003 and even 1994, according to Anne Shortall from the law firm undertaking the class action, “But it appears that the drug companies had information even quite a long time prior to that from studies they had done on patients in regard to the manufacture of the drug” (1).

There is no advice on compulsive behaviour side effects about Cabaser (2).

References:

1. ((http://www.abc.net.au/news/stories/2008…)

2. ((http://www.pfizer.com.au/ProductDetails…)

From sciencedaily.com

Doctors know an impaired sense of smell is an early indicator of Parkinsons Disease. Now they want to know if a smell test can help determine if people with no symptoms eventually develop the disease.

The analogy would be like diagnosing coronary artery disease before the heart attack, says Dr. Kapil Sethi, director of the Movement Disorders Program at the Medical College of Georgia and a lead investigator the Parkinsons Associated Risk Syndrome Study. With Parkinsons, we are dependent on the presence of motor symptoms like tremors, stiffness and slowness in order to diagnose it. By that time you have lost 50 to 60 percent of your dopaminergic cells, which make dopamine and are key to movement control. The question becomes, is there a window between when you had non-motor symptoms like loss of smell and when you begin to demonstrate clinical motor symptoms?

Dr. Sethi and researchers at 17 other sites across the country will recruit 15,000 close relatives of Parkinsons patients as part of the study, which is being led by the Institute for Neurodegenerative Disorders and the University of Pennsylvania.

By testing those with a family history of the disease, we have an enriched population, he says. We already know that those people are more at risk. To enrich the sample even further, well test their sense of smell. Its not just the essence of a sense of smell that is different in these people. Its a quantitative decrease in their ability to distinguish odors.

Patients will be given the University of Pennsylvanias Smell Identification Test, which tests for 40 common odors and has been used to detect the first signs of neurodegenerative disorders.

People with a normal sense of smell who take the test can usually identify around 35 odors correctly. Parkinsons patients typically can only identify 20 or less.

The study will also help determine if the smell test can also predict who will get Parkinsons. We believe that if youre a person who is going to develop Parkinsons, youll also score lower than others, Dr. Sethi says.

Based on the results of the smell test, study participants will be divided into two groups, those with a normal sense of smell and those without. Both groups will undergo functional neuroimaging analyses at the Institute for Neurodegenerative Disorders in New Haven. Functional neuroimaging can identify changes in brain activity associated with Parkinsons.

Both also will be clinically examined by a movement disorder specialist and followed for three to five years.

We believe that a proportion of those who have the deteriorated sense of smell will develop Parkinsons over the next two or three years, Dr. Sethi says.

Study participants also will be asked about other common symptoms of the disease that may be present prior to the telltale motor symptoms. For example, people with Parkinsons and other neurological diseases often suffer from a sleep disorder called REM Behavior Disorder, which causes them to act out their dreams.

While most people are paralyzed when they dream so they cant hurt themselves or others, people with Parkinsons are not, Dr. Sethi says. They yell, scream and kick. No one knows why, but half of the people who have this sleep disorder will develop Parkinsons or a similar disease.

Questions about excessive daytime sleepiness and anxiety and constipation and other pre-symptoms of Parkinsons also will be asked.

The goal is to give someone a degree of risk based on one or multiple factors, Dr. Sethi says. We dont know specific numbers now, but hopefully, in the future, we will be able to tell people who have a deteriorated sense of smell and the sleep disorder specifically how much their risk goes up.

The long-term goal, he says, is to develop prevention strategies once risk is established.

The study is open to those 50 or older who do not have Parkinson’s but have a mother, father, child or sibling with the disease. For more information, call the MCG Movement Disorders Program at 706-721-2798 or the Institute for Neurodegenerative Disorders 877-401-4300.

From MedPage Today

Exposure to pesticides increases the risk of Parkinson’s disease by about 70%, researchers here reported.

Action Points

Explain to interested patients that mounting evidence appears to implicate certain pesticides used in agriculture and for home insect control in the development of Parkinson’s disease, although the reasons for the association are still not known.

Inform patients that pesticide exposure can manifest as respiratory problems, gastrointestinal disease, headache, dizziness, confusion, skin problems, eye problems, and many other nonspecific conditions.

Among more than 140,000 men and women followed through 2001 as part of a cancer prevention study, those who reported being exposed to pesticides or herbicides before 1982 had a 70% higher rate of Parkinson’s disease 10 to 20 years after the initial exposure, reported Alberto Ascherio, M.D., Dr.Ph., of the Harvard School of Public Health, and colleagues.

The risk was highest among people with occupational exposure to pesticides, such as farmers and ranchers. There were no significant associations between Parkinson’s disease and other occupational exposures, such as asbestos, acids and solvents, coal, stone dust, or other materials, the investigators reported in the July issue of the Annals of Neurology.

The findings echo a similar but smaller recent study by Mayo Clinic researchers. In that study, the Mayo investigators found that men who have been exposed to pesticides are more than twice as likely to develop Parkinson’s disease as men who have managed to avoid contact with the toxic chemicals, reported Walter A. Rocca, M.D., M.P.H. and colleagues in the online edition of Movement Disorders.

In both the Mayo and Harvard studies, the Parkinson’s risk from reported pesticide exposure was equally high among farmers and non-farmers, and in both studies there was no elevated risk associated with exposure to any other categories of occupational exposures or household or industrial chemicals.

The Harvard investigators prospectively evaluated U.S. men and women who were part of the Cancer Prevention Study II Nutrition cohort started in 1992 by the American Cancer Society. Of this group, 143,325 who returned study surveys in 2001 and who did not have a diagnosis of Parkinson’s or parkinsonian symptoms at baseline were included.

A total of 7,864 participants (5.7%) reported exposure to pesticides, including 5,203 men and 2,661 women. In all, 1,956 participants fell into the category of farmers, ranchers, or fishermen, and people in this group had a 14-fold greater likelihood of pesticide exposure compared with those in other occupations. Blue collar workers were twice as likely as others to be exposed to pesticides.

The authors found that in an analysis adjusted for age, gender, and smoking status (current, past, or never), the relative risk for pesticide exposure and Parkinson’s was 1.7 (95% confidence interval, 1.2-2.3, P0.002).

Among the 2,308 participants who reported duration of pesticide exposure, the risks were not significantly different between those who reported exposure for more than a decade (relative risk 2.3, 95% CI, 1.1-4.9) or for less than 10 years (2,1, 95% CI, 0.7-6.5).

The authors noted that chemicals commonly used as pesticides in the U.S. have been shown to cause degeneration of dopaminergic neurons in the substantia nigra and to produce neurologic abnormalities when administered to experimental animals at high doses.

In addition, “in postmortem studies, higher levels of organochlorine insecticides have been found in the substantia nigra or striatum of individuals with Parkinson’s disease,” the authors wrote. “This finding reflects that organochlorine insecticides, unlike organophosphates and most other pesticides, persist in tissues many years after cessation of exposure.”

In autopsy studies to which the authors refer, significantly higher levels of organochlorines were found in the brains of people with Parkinson’s disease than in those with Alzheimer’s disease, Lewy-body dementia, or in nondemented patients.

Organochlorine pesticides include DDT (banned for use in the United States, but still in use in some developing nations), chlordane, lindane and toxaphene. This chemical group also includes polychlorinated biphenyls (PCBs) which are not pesticides but are classified as hazardous industrial pollutants.

The authors acknowledged that the study is limited by a lack of specifics on the duration, frequency, and intensity of pesticide exposure of information about the specific chemicals that participants were exposed to.

Nonetheless, the large sample size, prospective design and availability of information on potential confounding factors provide a strong foundation for their conclusions, they wrote.

They also pointed out that while pesticides could be a marker of other aspects of rural living, farmers not exposed to pesticides were not at increased risk, further evidence of a direct effect.

This suggests a link between the illness and depression, anxiety disorders, researchers say