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State of Parkinsonís Science is Focus of PDFís 50th Anniversary Symposium
Parkinson’s disease (PD) has long been diagnosed by classic motor symptoms — rigidity, slow movements, and tremor — that occur upon the death of certain cells in the brain. Since these cells normally control the body’s movements by producing a chemical messenger called dopamine, most therapies to date have been aimed at restoring dopamine in order to alleviate the motor symptoms of PD.
In recent years, scientists and clinicians have revised this traditional approach to PD.
“It’s increasingly recognized that Parkinson’s disease is not just a dopamine deficiency disorder,” said Stanley Fahn, M.D., Scientific Director of the Parkinson’s Disease Foundation (PDF), in the keynote address at PDF’s 50th Anniversary Educational Symposium, held October 11 and 12, 2007 in downtown Manhattan.
The state of Parkinson’s science was the focus of discussions at the symposium, which brought together more than 700 physicians, scientists, allied health professionals, caregivers, and people with Parkinson’s. Organized along two parallel tracks, one featuring sessions devoted to basic research and the other focusing on more clinical/practical aspects of the disease, the program gave people with PD the opportunity to ask questions of researchers doing cutting-edge science, while scientists could learn about the complexities of daily life with the disease.
Over the two days, speakers presented research to this multidisciplinary audience and asked: what successes have we seen in the last 10 years, and what can we expect in the coming decade?
According to Dr. Fahn, an explosion in scientific literature since the 1990s (nearly 22,500 articles related to PD have been published) has led to a change in thinking about how Parkinson’s begins and progresses. Studies demonstrate that PD is set in motion long before cell death in the brain affects movement. In fact, early nonmotor symptoms like loss of smell and constipation may signal nervous system damage outside the brain’s movement centers, and even outside the brain.
This broader approach opens the door to earlier diagnosis and new therapies that may slow the progress of PD, as well as treat its symptoms. It has also increased the attention placed on nonmotor symptoms of Parkinson’s and the commitment of health professionals to addressing them, thereby improving the quality of life for people with the disease.
Genetics Leads the Way
In 1997, scientists reported the discovery of the first gene found to be involved in Parkinson’s. It was the gene for alpha-synuclein, the protein that goes awry to form Lewy bodies, the accumulation of which is the hallmark of PD in people who have died with the disease.
Just 10 years later, researchers have identified as many as 13 genes that are related to PD. One that has attracted much attention is Parkin, in which mutations have been associated with symptoms of early onset PD. Mutations of LRRK2, the most common Parkinson’s-related gene, are found in about 10 percent of PD cases where there is no family history of the disease. Studies on the genes PINK1 and DJ-1, are leading to new insights in how dopamine neurons work.
When people with Parkinson’s asked whether they should have genetic tests, speakers said that the answer for most people at this time is probably no. The test is expensive and even a positive result neither changes the way Parkinson’s is treated, nor predicts how or when disease will progress. On the other hand, by participating in an organized genetic research project, people with PD and their families contribute to scientists’ broader understanding of the disease. Although few people have PD that is caused purely by malfunctioning genes, studying rare forms of the disease helps shed light on the molecular and cellular processes common to all. In turn, this knowledge is leading to new approaches to diagnosis and treatment. (To learn more about ongoing clinical research, please visit www.PDtrials.org.)
While genes certainly play a role, Dr. Caroline M. Tanner, of The Parkinson’s Institute forcefully communicated that, “genetics loads the gun, environment pulls the trigger.” Pinpointing and measuring the precise contribution of environmental factors — which can include exposure to chemicals, infections, and aspects of lifestyle — is difficult to do with current knowledge. MPTP is the only substance that has been proven to cause Parkinsonian motor symptoms. Scientists have long suspected that exposure to certain chemical pesticides with chemical structures similar to MPTP, such as paraquat, rotenone, and organochlorines, can also set off PD. Dr. Tanner hopes to settle that question in a study now underway that focuses on California farmers whose pesticide and herbicide exposures have been well documented.
How Does Parkinson’s Disease Begin?
By the time a person with Parkinson’s develops tremor or stiffness, half of the dopamine-producing cells in the brain have already died. Scientists are now questioning what biological events precede this cell death.
Research from the last decade points to a “preclinical” phase for PD — a period during which cell death is occurring but physical symptoms are not yet evident. In this phase, cell damage begins in areas of the brain that control activities like heartbeat, digestion, and smell. Later, the damage moves to the areas that are responsible for moving and thinking. If scientists can find ways to measure these earlier changes, they can develop ways to predict who is at risk for PD.
In particular, researchers have found changes in the olfactory bulb, the part of the brain that processes smell. “Loss of smell seems to be very specific for Parkinson’s disease — it may be a very early marker,” says Dr. Matthew Stern, of the University of Pennsylvania. Dr. Stern leads a study in which a scratch-and-sniff test for smell loss is being studied on thousands of people who have relatives living with Parkinson’s, and who therefore have a somewhat higher risk of developing the disease than the general population. Combined with other risk factors, the smell test may point to ways of predicting a person’s chances of developing Parkinson’s disease and diagnosing it early.
New Directions in Therapy
Levodopa, a breakthrough at the time of its arrival in the 1960s, remains the gold standard for treating PD. Certainly, the way that levodopa is used has changed. Doctors are now able to delay its use for several years and use it in combination with other drugs to enhance and prolong its positive effects.
In the meantime, new therapies show promise in treating the disease differently. For instance, could the progress of PD be slowed or even stopped? Scientists call this idea “neuroprotection.” This tantalizing goal is not yet a reality, but a variety of approaches show potential.
A clinical trial is currently underway to assess the neuroprotective potential of Coenzyme Q10, a substance that occurs naturally in the body and that is available as a supplement both over the counter and by prescription. Tests so far have proven that it is safe. Within a year or so, scientists will know whether it is effective, and if so, at what dose.
Dr. Ira Shoulson of the University of Rochester School of Medicine and co-Founder of the Parkinson Study Group gave an update on the halted trial of the neuroprotective experimental drug, CEP-1347, on which the PD community had pinned great hope. Dr. Shoulson reported that, while the study’s outcome was disappointing in that the treatment did not prove successful, additional studies planned for the original clinical trial group may be incredibly valuable for the future. To date, 65 percent of participants from the original PRECEPT trial have agreed to allow their data to be used in further investigations about how Parkinson’s progresses, and also in testing other potential treatments. Since the group represents one of the largest and best characterized databases ever compiled for PD, this PostCEPT data will provide important information for the PD community.
Gene therapy, a surgical technique that injects a specific gene deep into the brain (often by encasing it in a harmless virus that can correctly deliver it) offers another approach to slowing, and perhaps even reversing, the progress of PD. A Phase II clinical trial is now underway to test the injection of Cere-120, which consists of a virus carrying the gene neurturin. Cere-120 has been shown to alleviate symptoms in people with PD by improving the health of dopamine producing cells. Scientists at Rush University Medical Center, with Ceregene, Inc., lead the study. If the therapy works, researchers anticipate that its beneficial effects will be long lasting.
Cell transplantation is another surgical technique that aims to re-invigorate the brain’s ability to make dopamine. Using fetal cell transplants, researchers have achieved limited success with this technique since the 1980s. Today scientists are looking at the possibility of using stem cells to carry growth factors to the part of the brain that produces the all-important dopamine. Dr. Anders Bjorklund, of Lund University, reported that because stem cells can be standardized, and a reliable supply can be generated, they hold promise as the next step in cell transplantation research.
Another important therapeutic advance discussed was deep brain stimulation (DBS), a surgical option that has been found to be very effective for some patients, but not suited for all. The PDF symposium featured presentations on how DBS can improve gait and posture in people with severe motor symptoms.
More Than a Physical Disease
As people with Parkinson’s know well, even though “some forms of therapy address motor symptoms, you’re left with other symptoms,” said Dr. Fahn.
The symposium showed a true shift in the way Parkinson’s is viewed by doctors and patients alike. The community increasingly recognizes that nonmotor symptoms such as depression, constipation, pain, urinary problems, sleep disorders, sweating, fatigue, dementia, and others, drastically affect quality of life for people with Parkinson’s, their caregivers, and their families.
The symposium featured sessions by clinical neurologists, nutritionists, physical therapists, speech pathologists, nurses, and others — all of whom can provide therapies, and in some cases medications, that ease the nonphysical effects of PD.
Julie Carter, R.N., M.S., of Oregon Health and Science University, told her audience that depression is the most common nonmotor symptom seen in those with PD, affecting up to 50 percent of those with the disease — but it is also under-recognized and under-treated. Therefore, it is vital for patients themselves, family members and clinicians to look for signs of depression in order to treat it. Dr. Giselle Petzinger, presented engaging research on the effects of exercise — showing that regular physical activity improves physical mobility of patients with PD. Her continued research will investigate whether exercise can actually remodel the brain as well.
While the symposium brought together various populations of the PD community and hopefully provided resources and practical tips to people affected by PD — it also looked ahead to assess the most promising science. As Executive Director, Robin Elliott continually stressed throughout the event, the symposium represented a recommitment to PDF’s primary goals: development of new treatments and pursuit of the cure.
A webcast of almost all the symposium sessions will be available on PDF’s website for one year. To learn more or view these exciting sessions, please visit www.pdf.org/en/50th_Symposium.