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Chasing the Cure: A Decade of Advances in Parkinson's Disease Research
By Stanley Fahn, M.D.
“What’s happening in research on Parkinson’s disease (PD)?” This question is always uppermost on the minds of people with Parkinson’s and their family members. To answer it, I have looked back at the research conducted in the past decade or so. It turns out that between 1997 and 2007, more than 23,000 scientific articles addressing Parkinson’s were published.
This large number reflects the excitement stirring in this field. But what did the research yield? While we have much further to go in our understanding of Parkinson’s disease and towards our goal of finding a cure, I expect that you will be as impressed as I am by the serious investment of time and resources that is going into this important research.
Genetic and Environmental Causes of PD
To me, the most exciting and important area of PD research during this period is genetics. Although few cases of Parkinson’s disease can be attributed to genes alone, identifying the types of genetic mutations that lead to PD has given researchers tools for unraveling the molecular mechanisms that underlie the disease.
In 1997, scientists described the first gene known to be mutated, or changed, in PD. The gene named SNCA, or PARK1 (the first in a series of PARK genes that now number more than a dozen) codes for alpha-synuclein, a protein that we have since learned may play a very important role in the development of PD. While mutations in this gene are very rare, the discovery that an alteration of alpha-synuclein is involved in PD spurred researchers to study it. They found that this protein is present in the Lewy body, a foreign inclusion in neurons that is the pathologic hallmark for PD.
Another important genetic discovery related to alpha-synuclein was that the mutation known as PARK4 was actually a triplication of the normal SNCA gene, meaning that people with PARK4 had extra copies of the gene and thus, an excess of normal alpha-synuclein. So, too much alpha-synuclein — and not just an abnormal form of the protein — can cause Parkinson’s, albeit in very few people. Partly because of this discovery, much research in the last decade has focused at the molecular level on the mechanisms by which the alpha-synuclein protein contributes to the death of dopamine neurons. It is now understood as one of three elements within the dopamine neuron — the other two are dopamine and calcium — that interact to cause neurodegeneration.
There are several other genes that have been implicated in PD. Some rare mutations are implicated in the onset of PD at a young age, usually before the age of 30; these genes are PARK2, PARK6 and PARK7. Their abnormal gene products appear to affect the function of the energy factory of the cell — the mitochondrion.
The most common mutations that contribute to Parkinson’s occur in the gene known as PARK8 or LRRK2. Mutations in many different parts of this gene have been discovered, and they can occur in people who do not have a family history of PD. In fact, mutations in this gene have been identified in more than two percent of people with Parkinson’s in North America and England, who do not have a family history of the disease. They are found even more frequently among people with Parkinson’s disease who are of Portuguese, Spanish, Ashkenazi Jewish and North African descent. It is not yet understood how the abnormal LRRK2 protein causes PD. This should be an area of intense research in the future.
Since Parkinson’s usually cannot be attributed entirely to genetics, scientists have also studied environmental contributions. A large study of identical twins in which at least one member of the pair was diagnosed with PD helped to sort out the relative genetic and environmental contributions. The researchers found that when PD was diagnosed before the age of 50, it was much more likely to have a strong genetic component than when it was diagnosed later in life.
Environmental toxins have long been considered a potential trigger for PD and much research has focused on pesticides. From research on laboratory animals and also from studies that collected data on large numbers of people who were exposed to pesticides (known as epidemiological studies), we have learned that the chemicals rotenone and paraquat contribute to PD. But the relationship of pesticide exposure to Parkinson’s remains unresolved, and the search for an explanation continues.
Scientists are also investigating whether an underlying genetic predisposition could combine with pesticide exposure to result in PD. In the meantime, some things in the environment have been shown to correlate with a lower risk of Parkinson’s. Smoking cigarettes is one (although it can lead to other health problems); others are drinking coffee, having higher levels of uric acid in the bloodstream, and having gout.
How PD Begins: A New Theory
We have long known that the motor symptoms of Parkinson’s begin when dopamine-producing cells die in a part of the brain called the substantia nigra. This is often the point at which people with Parkinson’s first receive a diagnosis. Then, along came a theory suggesting that at this point, people are already at a relatively advanced stage of the disease, and that PD actually starts earlier, with changes in other areas of the brain and elsewhere in the body.
The theory was first proposed a few years ago by the German researcher Heiko Braak, M.D. He and his colleagues examined the autopsied brains of people who had died with Parkinson’s and found that alpha-synuclein protein accumulated in areas other than the substantia nigra. These areas, including the pons and the medulla in the brainstem, control body functions such as digestion, heartbeat and the regulation of sleep. His team also found widespread deposits of alpha-synuclein in nerve cells in the gut.
These discoveries led Dr. Braak to propose that alpha-synuclein abnormalities begin to accumulate in “lower” regions of the nervous system, eventually reaching “higher” areas in the brain. Dr. Braak’s hypothesis has stimulated much discussion and debate among researchers. His observations may explain some of the nonmotor symptoms of PD, such as constipation, changes in sleep and mood and decreased sense of smell.
Beyond noting accumulations of alpha-synuclein, new research has shed light on other molecular mechanisms by which neurons degenerate in PD, including oxidative stress, alteration of the mitochondria and inflammation. The understanding of these processes has led to new ideas for developing therapies for Parkinson’s.
Diagnosing Parkinson’s and Measuring Its Progression
Partly because of Dr. Braak’s hypothesis, researchers are searching for biomarkers to detect PD before the motor symptoms become manifest.
One method that has shown promise is neuroimaging — that is, getting a picture of the brain using techniques known as positron emission tomography (PET) and single photon emission computed tomography (SPECT). In clinical trials evaluating people newly diagnosed with PD that also included one of these imaging techniques, ten to 15 percent of these individuals had scans without evidence of a dopaminergic deficit — meaning they did not have PD at all and there was some other cause of their tremor and slowness. These individuals did not respond to levodopa therapy. Some PET techniques have been helpful in differentiating PD from atypical parkinsonisms, such as multiple system atrophy and progressive supranuclear palsy. Such tools could be helpful in both diagnosing PD and treating it earlier in its progression.
Findings in the Clinic
James Parkinson’s original description of PD stated that the “senses and intellects” were “uninjured” in the disease. But we have known for many years that this is not the case, possibly because with modern treatment, people with PD live much longer than ever before. In the past decade, physicians have developed a keener awareness of nonmotor symptoms of Parkinson’s and their impact on quality of life for people with PD. These symptoms include personality changes such as the development of passivity, difficulty making decisions, loss of motivation, anxiety, depression and bradyphrenia (slowness in thinking). These and other nonmotor symptoms — including such problems as fatigue, sleep disturbances, constipation, bladder disturbances and changes in sensory perception — can become more serious when motor problems of PD are controlled with medications. Fortunately, many of these nonmotor symptoms can respond to treatment.
Effective medications that can reduce the severity of PD, however, are not always free of side-effects. Sometimes, serious adverse effects of hallucinations, delusions and paranoia can occur. The drug clozapine, not yet approved for PD, has been shown in clinical trials to ease such side-effects without aggravating Parkinsonian motor symptoms. In addition, in some people, PD medications known as dopamine agonists have been found to cause impulsive behaviors — most commonly pathologic gambling, compulsive eating and shopping — and hypersexuality. Reducing or stopping the medication eliminates these problems.
Researchers have learned that cognitive decline often occurs in people with PD when they reach an advanced age. This process has been traced to the presence of Lewy bodies in the brain’s cerebral cortex, the area that is responsible for reasoning and decision-making. One medication, rivastigmine (Exelon®), is currently approved for and has been shown to be modestly effective for treating dementia in people with Parkinson’s.
Advances in Treating PD
With therapies already in hand to control the symptoms of PD, the focus in recent years has been a search for medications that slow the rate at which PD progresses. Some drugs that looked promising based on testing in animals turned out not to be effective in humans. One class of drugs that may be effective in this regard is the MAO-B inhibitors. One of these is selegiline (Eldepryl®, Zelapar®); another is rasagiline (Azilect®).
Other agents, Coenzyme Q10 and creatine, are still in clinical trials. In other reassuring news, scientists found that levodopa — which was long suspected of worsening oxidative stress and possibly hastening the progression of PD — in fact may slow it down. The challenge of slowing down the progression of PD is also being addressed by scientists who are interested in exploring the neuroprotective value of physical exercise.
A number of controlled clinical trials have tested new therapies that control, but do not slow, symptoms. In general, researchers found a trade-off between the new treatments and levodopa, the gold standard: that is, the drugs that reduced motor fluctuations and dyskinesias (involuntary twisting and writhing movements) were less powerful than levodopa in alleviating Parkinsonian symptoms. One new medication, rotigotine (Neupro®), a dopamine agonist administered by a skin patch, came to market, but is currently unavailable in the US due to manufacturing problems.
Also, in the last decade, surgical deep brain stimulation (DBS) has been validated as an effective therapy for reducing dyskinesias and motor fluctuations in people who otherwise respond well to levodopa. However, many questions remain unanswered, including optimal timing of surgery and the long term outcome (more than five years after surgery) of the procedure. Other surgical approaches to therapy, including gene therapy, are now in clinical trials.
A Wealth of Discoveries
Space limitation allows me to discuss only a tiny fraction of what we have discovered about PD during the last decade. I could go on to write, for example, about studies on biomarkers that may someday help predict PD risk. This and other discoveries will be in the news in the near future. Parkinson’s research is a growing field, and with each year we will see advances in both laboratory and clinical science.
Stanley Fahn, M.D., is the H. Houston Merritt Professor of Neurology and Director of the Center for Parkinson's Disease and Other Movement Disorders at Columbia University. He has served as the Scientific Director of PDF since 1973.