Dr. J. William Langston, M.D. is President of the Parkinson's Institute. A graduate of the University of Missouri Medical School, he completed his internship and residency in Neurology at Stanford Medical School and received additional training at the Meninger Foundation in Topeka, Kansas, and the National Institute of Neurology in London, England. He has served as chief of the Department of Neurology for the Santa Clara Valley Medical Center, as a member of the faculty at Stanford University, and as a Senior Scientist with the California Institute for Medical Research. A diplomate of the American Board of Psychiatry and Neurology, Dr. Langston has authored over 180 publications, mainly in the areas of Parkinson's disease, neurotoxicology and pharmacology, aging, movement disorders, and neurodegenerative diseases. Dr. Langston is also the co-author of The Case of the Frozen Addicts, a book which describes the discovery of MPTP.
What is the Parkinson's Institute and how was it started?
The Parkinson's Institute is a nonprofit organization that represents a unique blend of clinical research, basic research and day-to-day patient care. We have one of the largest movement disorders clinics in north America, but also have a full basic research laboratory where almost every aspect of the disease is under study. What's quite powerful about this approach is that discoveries in the laboratory can quickly be translated to the clinic and vice versa -- observations in the clinic can be taken to the laboratory for further study. So it is a very effective way to do disease-oriented research and from that standpoint it's a fairly unique organization.
How long has the Institute been in existence?
This is our tenth anniversary. We were founded in 1988. We started in a small one-room trailer but have since developed into a fully integrated, multidisciplinary institute with a mission of finding the cause and cure of Parkinson's disease.
Would you give us a definition of Parkinson's disease?
Parkinson's disease is one of the two major degenerative diseases of the brain associated with aging. Alzheimer's disease is the other. Different from Alzheimer's, however, is the fact that Parkinson's disease robs patients of their ability to move normally and in the majority of the cases, leaves thinking intact. The disease is slowly progressive and there is no known cure for it at the current time. Clinically, it is associated with a variety of motor symptoms including slowness of movement, difficulty with walking (typically characterized by a slow, shuffling gate), tremor which occurs at rest, and a loss of balance causing patients to have a tendency to fall.
There are a wide variety of treatments now available for Parkinson's disease as opposed to Alzheimer's where there is really very little. In fact, it would be fair to say that the major enemy in treating Parkinson's disease at the current time is probably less the ability to manage symptoms, than it is to avoid side effects of the drugs we use to treat it. These side effects of therapy often force us to decrease doses of medication at a time when patients actually need it more than ever. So, a lot of what we do in treating Parkinson's disease is directed as much towards avoiding the side effects of therapy as it is to try to make the patient better on a day-to-day basis.
What are some of the current treatment protocols?
There are a variety of medications available for Parkinson's disease. The backbone of therapy is still L-DOPA, commercially available as Sinemet and also in generic forms. Very few patients can go for a long period of time without L-DOPA after the diagnosis of Parkinson's disease is made. L-DOPA is called a dopamine precursor because the brain converts it into dopamine. Dopamine is depleted in the brain of patients with Parkinson's disease. It is not possible to give dopamine directly because it does not cross the blood brain barrier, whereas the precursor L-DOPA does.
A second class of drugs used to treat Parkinson's disease are the so-called dopamine agonists. These are completely different compounds that do not require transformation into dopamine, but rather stimulate dopamine receptors directly. Agonists tend to be longer acting than L-DOPA, and tend to both accentuate and smooth out its effects. Currently available agonists include bromocriptine (Parlodel), pergolide (Permax), pramipexol (Mirapex) and ropinerol (Requip).
In addition to L-DOPA and dopamine agonists, there are a number of other pharmacologic approaches to the disease. Anticholingeric agents represent another of the class of drugs used to treat Parkinson's disease, but they are less used now because of their side-effects, particularly on memory and thinking. Another category of drugs are monoamine oxidase inhibitors. One of these, known as selegiline (Eldepryl), has been suggested to slow the progress of Parkinson's disease. While this remains to be unequivocally proven, because of its relative safety in newly diagnosed patients who are not on other forms of treatment, many physicians do use it early on to try to help slow down the process. This drug also makes L-DOPA therapy more effective by blocking the breakdown of dopamine.
Very recently, an entirely new class of drugs have begun reaching the market, called COMT inhibitors. These drugs block the metabolism of L-DOPA itself in the periphery and perhaps to some degree in the brain. There is solid evidence that they enhance the effectiveness of L-DOPA, possibly with less risk of side-effects than by simply increasing the dose of L-DOPA itself. One of these drugs, tolcopone (Tasmar) is now available for use.
So, we do have large panoply of drugs - the art of managing Parkinson's is when to start those drugs and how to apply them to get a longer, better effect while also avoiding side effects.
What is the length of time that someone would be on any of these drugs or combinations of these drugs?
Anyone who has Parkinson's disease, once they reach a point where they need symptomatic therapy, is going to be on one or more of these drugs the rest of their life. Most patients, once they start L-DOPA, will never go off the drug. The agonists tend to be added later, although in younger patients I start with agonists.
Beside the medication management issue, are there other treatment protocols like direct therapeutic interventions or other aspects of caring for patients with Parkinson's that the Institute is recommending in terms of family care?
Surgical interventions represent an exciting new arena for the treatment of Parkinson's disease. The one that is attracting the most interest right now is a procedure called deep-brain stimulation. This technique involves placing electrodes in specific brain areas, where they are left and connected to a pacemaker which is used to turn the electrodes on and off and set the stimulus parameters. This procedure has already been approved by the FDA for treatment of tremor by placing the electrode in an area known as the thalamus. However, a much more exciting possibility is to use this approach to treat most, if not all, of the symptoms of Parkinson's disease by stimulating a different area of the brain known as the subthalamic nucleus, bilaterally. In some cases, it has been possible to dramatically reduce the symptoms of Parkinson's disease with this type of brain stimulation, and a few patients have even been able to stop all antiparkinsonian medications. This procedure is still experimental, and the long-term effects and likelihood of obtaining a good or excellent response are still unknown. The area of neurotransplantation is also of interest, but the research is moving quite slowly, in part at least because of issues regarding limited supply of tissue, and the lack of viable alternatives to fetal tissue at the present time.
Moving out of the area of pharmacological and surgical therapy, there are many things that one can do for Parkinson's patients. By and large the most important one in my opinion is exercise. Exercise has a very positive effect on a day-to-day function. Short of medical therapy, if there's one thing we can encourage patients to do, it is to participate in exercise programs - to stay active and to keep their bodies going. This is a very important point. Diet is important. One has to be careful with protein because it interferes with L-DOPA transport into the brain. One needs protein to live, so patients can't stop eating protein, but it is possible to move protein intake around during the day to better facilitate function at other times of the day. Overall, we really encourage patients to try to stay active and maintain as much of a normal life routine as they can.
Are there other areas of research going on in the field that you'd like to comment on?
One area that is really important is research on the cause of the disease. There are now two families where parkinsonism has been found to be inherited in a dominant form. When the identity of the responsible mutation was announced last year, it was widely reported in the news media that the gene for Parkinson's disease had been found, and that led many to believe that their Parkinson's was going to be passed on to their children. I think it's very important to emphasize that this genetic form of parkinsonism is restricted to date to a handful of families, so far as we know. So, heredity appears to be a rare cause of Parkinson's disease.
We recently published a study in which we examined 100 consecutive younger-onset (under the age of 50) Parkinson's patients for the gene that is now known to cause a form of parkinsonism. None of the patients in our study were found to carry this gene. So, the gene that has been so widely reported is actually a very rare cause of the disease. In fact, most patients do not need genetic testing and probably should not worry about their children inheriting the disease. I would say only in situations where there are multiple-affected immediate family members should it even be considered.
Are there other areas of research and trends that you see as promising that are in clinical trials now?
There is one more I would mention that is in the experimental stage at this time, but could be very promising and that is the area of using growth factors. There are so-called neurotrophic factors that seem to stimulate neurons that are not functioning and can actually protect neurons from damage. There are now a number of such compounds that have been found to stimulate dopaminergic neurons. There is great hope that those compounds might be used to, for lack of a better word, rejuvenate neurons that are damaged or are not functioning in Parkinson's disease (or, put another way, to turn them back on). The reason this is so exciting is that there is good evidence that there are many neurons in the brains of Parkinson's patients that have not died yet, but are no longer functioning. It's conceivable that if you could turn those neurons back on, you might actually be able to bring patients back out of a symptomatic state because there is a fine line as to how much dopamine you need to lose to get symptoms. So, there's a lot of interest in the possibility that these neurotrophic factors could be used not only to try to halt progression but actually, to some degree, reverse the symptoms. That's theoretical. There is a lot of experimental evidence that suggests it could be done and there is at least one clinical trial currently going on in humans to test this hypothesis using a growth factor known as GDNF.
It sounds like there is a fair amount of study going on.
If you looked at the field of Parkinson's disease 15 years ago, it was a barren land in terms of research. Now we have so many new leads that it is hard to know which ones to follow. The good news for patients is that it's a very exciting time in the history of Parkinson's disease research and that in the long run, this cannot help but benefit patients with Parkinson's disease. So stay tuned.
Interview Date: March 1998
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