Parkinson's Disease

Biology 202
1998 First Web Reports
On Serendip

Five years ago, she could still show the world her pleasant demeanor with a smile. Four years ago, she could no longer smile, but she was still able to walk upright. Two years ago, she could no longer walk without aid from a walker, but she could still find her mouth with a fork while eating dinner. Eighteen months ago, she could no longer eat under her own power, as the involuntary tremors in her hands flung the food from the fork long before it reached her mouth. A year ago, my grandmother died. She was diagnosed with Parkinson's Disease (PD) five years ago, and slowly deteriorated for four years until her death. She was given myriad drugs, but none seemed to help for more than a month, leaving her in worse condition after the affects wore off. Herein lies the mystery of Parkinson's Disease.

Researchers have made great progress in uncovering the etiology of this mysterious disease. Before summarizing some of the current theories on the cause of PD, however, it is necessary to describe some clinical observations of patients. Symptoms of PD include tremors, rigidity, bradikinesia (slowness of movement) and loss of postural control (1). It has been found that patients who show these symptoms for PD have an eighty percent reduction in the levels of both dopamine (a neurotransmitter in the Substantia Nigra) and dopaminergic neurons (neurons that contain dopamine receptors) (1).

There are currently four main theories on the cause of Parkinson's Disease: (a) Oxidation of molecules such as iron in the Substantia Nigra by free radicals kill the dopaminergic neurons (1); (b) environmental toxins similar to MPTP (a compound related to the painkiller Demerol), which have been shown to cause Parkonsinism-like symptoms, kill the neurons (1,2); (c) a mysteriously increased rate of dopaminergic neuronal apoptosis in some individuals (1); and (d) Genetic influence, as the penetrance of PD has been observed at higher levels within some families (1). There is evidence for all of these theories, although the most concrete evidence comes from a study that showed increased levels of iron in the Substantia Nigra in PD patients (1). While this study proved nothing, it provided further evidence for a powerful oxidizing agent, such as a free radical, involved in the degeneration of dopaminergic neurons. The true cause of PD is most likely a combination of all four of these theories, along with revisions made by the large amount of yet undiscovered information.

There has been a great deal of research done on finding a cure for the disease, with marginal success. A drug thought by many to be a miracle drug for PD was L-dopa. L-dopa is the natural precursor for dopamine in its metabolism in the brain (which ends in the production of epinephrine). It was used as a treatment instead of dopamine to replace dopamine levels in the brain because it can cross the blood-brain barrier, and so could be applied intravenously. For a long time, L-dopa seemed to be working wonderfully, alleviating many of the symptoms of PD (3). Before long, however, it became apparent that L-Dopa was causing multiple side effects (4,5,6), including the “freezing phenomenon” in many long-term users. The “freezing phenomenon” describes a state in which the patient becomes unable to move his/her muscles (5). These side-effects resulted from the over-zealousness of researchers to find an easy answer to the Parkinson's problem. L-Dopa seemed to be a miracle drug because it erased many of the more obvious symptoms. However, it failed to make any progress in stopping the progression of the disease, and seemingly made it even worse. This evidence seems to indicate that PD may potentially be caused by an increased toxicity of the dopamine to the dopaminergic neurons, although there are no web pages to back up this hypothesis. This may be caused by any or all the pre-existing theories mentioned above. For example, take as a model someone born with a genetic predisposition to a reduced level of antioxidants (which help to eliminate free radicals). The dopaminergic neurons of this person would then have an impaired ability to rid themselves of the free radicals normally associated with dopamine metabolism. Thus, there would be a greatly increased level of free-radical dopamine metabolites, which could potentially harm the neurons. In this theory, L-dopa would actually accelerate the progression of the disease by creating even more free radicals in the Substantia Nigra, more rapidly killing dopaminergic neurons.

Other treatments are now being used, but no absolute cures have been found. Despite the long-term failure of L-dopa, it is still one of the main PD treatments. Its dosage and side effects, however, are much more closely monitored than when L-dopa was first administered. Other dopamine agonists (similar to L-dopa) are used to replace dopamine levels in the brain. None, however, have at this point been shown to work more effectively than L-dopa. Before L-dopa was discovered, surgery was used to treat PD. Recently, there has been a resurgence of surgical techniques such as Pallidotomy and Thalamotomy, in which legions are made in the patient's Globus Pallidus or Thalamus, respectively. While these surgical treatments relieve the symptoms in some patients, they are by no means universal. Experimental methods at this time include Deep Brain Stimulation, where electrodes are placed in the brain so as to stimulate the thalamus; and fetal tissue implants. Fetal tissue implants seem to show the most promise, as the fetal tissue has been shown not only to survive in the host, but to replace many of its damaged dopaminergic neurons (7). This technique, unfortunately, carries with it a host of ethical issues, and so will most likely never become a popular treatment.

PD research, therefore, has come a long way since the discovery of "The Shaking Palsy" by James Parkinson in 1817 (1). New, exciting treatments are produced at an ever-increasing rate. Unfortunately, a cure has yet to be found, but there seems to be a great deal of promise. My grandmother was a guinea pig. One can only hope that her illness provided information that brought us a step closer to a cure. Perhaps one day all of this research will pay off so that millions of elderly are spared the years of intense suffering my grandmother experienced.

WWW SOURCES

1. The Parkinson's Web

2. The Parkinson's Web

3. Increased neostriatal dopamine activity after intraperitoneal or intranasal administration of L-DOPA: on the role of benserazide pretreatment.

4. Novel therapeutic directions for Parkinson's disease.

5. [Freezing phenomenon in Parkinson disease]

6. Parkinson's disease: drug therapy.

7. Parkinson's Disease

Comments made prior to 2007

I am a neurologist who specializes in the treatment of Parkinson's disease. I read with dismay EO's article on Parkinson's Disease. From his description of his grandmother's condition, it seems likely that she did not have Parkinson's disease at all, but a related syndrome called Multiple Systems Atropy.

The article is riddled with inaccuracies. For example, he attributes "freezing" as being a side-effect of L-dopa. However, "freezing" is an effect of the disease process itself, not the drug. He suggests that L-dopa is toxic to neurons; a recent large double-blind study (the ELLDOPA study) demonstrated that L-dopa is NOT toxic to brain cells, and does not accelerate progression of the disease.

He also describes fetal tissue implants as "promising." In fact, these implants have been definitively shown NOT to be effective in treating Parkinson's disease, in a large double-blind study, and are in fact harmful.

In the disclaimer at the bottom, it's mentioned that this article is not designed to be authoritative. However, at this point, the article borders on frank misinformation, and could distress or harm people with Parkinson's disease and their caregivers. Please consider taking it down. Feel free to contact me about this at the above email address ... Alida Griffith, 25 March 2004