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More on Parkinson's Research

Parkinson's Research

Experts Explore Genetic Roots of the Disease and Side Effects From Medication in Two Clinical Trials

New York (Feb 18, 2010)

Older man's hands on a cane

Patients who visit NewYork-Presbyterian Hospital to be evaluated for Parkinson's disease (PD) or to confirm the diagnosis have the opportunity to register for a variety of clinical studies that are advancing the understanding of this disease. Current research is working to identify genetic causes of PD as well as a new understanding of side effects of PD medications.

Genetic Causes of Parkinson's Disease

"PD is considered to be a complex disorder meaning that there are multiple causes," said Roy N. Alcalay, MD, a Clinical Fellow supported by the Parkinson's Disease Foundation at the Center for Parkinson's Disease and Other Movement Disorders, NewYork-Presbyterian Hospital/Columbia University Medical Center. In addition to environmental causes, genetic mutations have been linked to PD, the most common of which are in the LRRK2, GBA, and Parkin genes.

Roy N. Alcalay, MD
Roy N. Alcalay, MD

Dr. Alcalay's research is focused on determining whether the different genetic mutations associated with PD are actually associated with different types of PD. His mentor, Dr. Karen Marder, recruited over 1,000 patients in a multicenter NIH-funded project. "Patients with PD are very heterogeneous. Some patients have a mild disease and progress very slowly and 40 years later do well despite having a lot of tremor, while some patients progress rapidly with the most concerning symptom being dementia/cognitive impairment," Dr. Alcalay said. "Is the multiple presentation and heterogeneity in the disease course the result of different causes of PD? Is it one disease or is it many?"

His recent research shows that patients with PD who have the LRRK2 G2019S mutation are more likely to have postural instability and gait difficulty than tremor. This mutation is found in approximately 18% of PD patients of Ashkenazi Jewish descent and 39% of patients of Northern African Arab descent. "The next step of the research, besides better defining the disease course of mutation carriers, is to see whether those genes educate us about the cellular mechanisms that cause PD so we can develop new medications to treat the disease. That is the overall goal of the genetics," Dr. Alcalay said.

At this point, "we don't recommend genetic testing," Dr. Alcalay said. The tests only indicate a genetic vulnerability and not that someone will necessarily develop PD. "Further research is necessary to determine the value of genetic testing," he noted.

Dopamine Agonist Withdrawal Syndrome

Recent research by Melissa J. Nirenberg, MD, PhD, the Associate Director of the Parkinson's Disease and Movement Disorders Institute at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, has identified severe withdrawal symptoms in certain patients with PD who tapered a dopamine agonist medication such as pramipexole (Mirapex) or ropinirole (Requip). These symptoms, which she likens to the withdrawal symptoms experienced by cocaine addicts, include anxiety, panic attacks, agoraphobia, depression, severe fatigue, sweating, lightheadedness, and nausea. The withdrawal symptoms were specific to the dopamine agonists, and not alleviated by other Parkinson's disease medications.

Melissa J. Nirenberg, MD, PhD
Melissa J. Nirenberg,
MD, PhD

Interestingly, withdrawal symptoms were only identified in patients who experienced impulse control disorders – uncontrolled behaviors such as compulsive eating, gambling, shopping, and hypersexuality – as a side effect of the dopamine agonist. When Dr. Nirenberg tried to wean these patients off of the medication, some of them developed severe withdrawal symptoms. "Most patients were eventually able to reduce the dopamine agonist dose considerably, but some were never able to discontinue the drug because of severe withdrawal symptoms," Dr. Nirenberg said. Those patients continue to have impulse control disorders, even though they are on a very low dosage of dopamine agonist. "They appear to have become sensitized to the dopamine agonist, such that they experience impulse control disorders even when maintained on a very low dosage."

The withdrawal symptoms also appear to be linked to a longer duration of medication use and greater cumulative medication exposure. Dr. Nirenberg is currently investigating if there is a way to predict who will develop compulsive behaviors, whether weaning patients off of the drugs at the first sign of compulsive behaviors is helpful, and whether there are alternative ways of treating impulse control disorders that will allow patients to continue taking the medications without experiencing these serious side effects.

In addition, Dr. Nirenberg is the site principal investigator for another study examining high-dose coenzyme Q10 in combination with high dose vitamin E to slow the progression of PD. NewYork-Presbyterian/Weill Cornell is the lead site for this large, phase III, multi-center, NIH-sponsored clinical research study.

Other Research

Other physicians at NewYork-Presbyterian are engaged in a variety of clinical trials on PD. Among the many trials are MRI studies investigating the way that PD medications affect the brain and learning, and imaging, blood, and genetics studies to identify biomarkers that can be used to diagnose PD in its earliest stages.

Dr. Alcalay suggested that patients visit the Parkinson's Centers at NewYork-Presbyterian even just to be entered into the clinical trials database so that they can be contacted if an appropriate clinical trial becomes available. Patients interested in learning about the Parkinson's Center at NewYork-Presbyterian/Columbia can arrange an appointment with Dr. Alcalay or his associates at 212-305-5558.

Patients who are interested in learning more about the Parkinson's Center at NewYork-Presbyterian/Weill Cornell and potential opportunities to participate in clinical research studies can schedule an appointment to see Dr. Nirenberg or one of her colleagues by calling 212-746-2584.

Contributing faculty for this article:

Roy N. Alcalay, MD, is a Clinical Fellow at the Center for Parkinson's Disease and Other Movement Disorders at NewYork-Presbyterian Hospital/Columbia University Medical Center. He will be named an Assistant Professor of Neurology at Columbia University College of Physicians and Surgeons in July of 2010.

Melissa J. Nirenberg, MD, PhD, is the Associate Director of the Parkinson's Disease and Movement Disorders Institute at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and an Assistant Professor of Neurology and Neuroscience at Weill Cornell Medical College.

References

Alcalay RN, Mejia-Santana H, Tang MX, et al. Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease. Arch Neurol. 2009;66(12):1517-1522. http://archneur.ama-assn.org/cgi/content/abstract/66/12/1517

Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol. 2010;67(1):58-63. http://archneur.ama-assn.org/cgi/content/abstract/67/1/58

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