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 effects wore off. Herein lies the mystery of Parkinsonās 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 Parkinsonism-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.
Now we are left with semi-effective
treatments for Parkinsonism, all of which seem to have dangerous side effects.
Why is it so difficult to find a cure for Parkinsonism? How is this
disease any different than other easily treatable disorders? One
factor leading to extreme difficulty in studying Parkinson's Disease is
that the age of onset is generally around 50 or 60 years old. By
the time patients show clear Parkinsonism symptoms, the disease has progressed
far beyond its point of no return. The only move in this case would
be to momentarily slow the symptomatic progression of the disease.
This was exactly what L-Dopa and all of its descendants accomplished, but
that is not good enough. From all of the evidence provided in this
paper, it has become clear that in order to successfully treat Parkinson's
Disease, one must administer a treatment near the onset of the disease,
not of the symptoms. This is obviously a tricky objective, as there
is yet no efficient way to diagnose this debilitating disease. This
sort of treatment would require that every seemingly healthy individual
in the country be tested for lowered levels of dopamine, which seems a
bit impractical.
I therefore propose that
a PD test be given to every newborn. Therefore, if PD begins its
progression at the earlier stages of development, this test will greatly
facilitate early PD studies. One potential problem with this test
is that it is quite possible the onset of the disease does not occur until
later in life, in which case PD tests would have to be given periodically
throughout everyone's life. I realize that this solution is a bit
extreme, but Parkinson's Disease leads to an extremely painful and embarrassing
condition. Not only is PD such an awful disease, but it is extremely
widespread, afflicting a large percentage of the population
Even more widespread than the disease, however, is the interest to talk
about PD, as is demonstrated by the thousands of Parkinsonism forums I
came across in my search on the net (8 is an example).
Another area of study that
could potentially lead to a cure is researching the genetic influence of
Parkinson's Disease (9, 10). If a PD gene
were found, it could lead to novel gene therapy techniques to treating
the disease. As far as I could tell from my research on PD, there
is not a great deal of research being done on its genetic characteristics,
as the general overview web pages did not even mention genetic influence
as a probable cause. There is one group of scientists, however, working
in Charlottesville, Virginia, who believe they have found the gene which,
when mutated, is responsible for the onset of PD (10).
They performed various tests on neuronal cell lines obtained from Parkinsonās
patients. They found that these neurons expressed severely depressed
levels of an enzyme called complex I, the first protein in the electron
transfer chain in the mitochondria. It has also been found that this
lowered level of complex I leads to an increase in the level of oxygen
radicals, which could easily kill off dopaminergic neurons, thus lowering
the level of dopamine.
An argument against genetic
inheritance of PD is that the disease seems too sporadic within families.
W. Davis Parker, professor of neurology at U.Va, explains, however, that
"the genes contained on mitochondrial DNA (mtDNA) exist independent of
nuclear DNA. In other words, this is a new principle of human genetics
that may explain why some diseases currently thought of as sporadic, like
Parkinson's, may in fact be inherited in an unorthodox way" (10).
Parker and his team are continuing research in order to target the specific
sequence of DNA which is mutated in Parkinson's patients.
If the DNA sequence were
to be found, gene therapy treatments would take off. There are various
types of gene therapy, but the basic premise is that one can "trick" a
cell into thinking artificially made DNA is its own. Therefore, with
the knowledge of the DNA sequence, one could create, in a test tube, an
unmutated complex I gene to be used for gene therapy. Since the state
of the PD gene could be attained in infants, it would be possible to administer
this treatment in early development, its most effective stage. Even
disregarding the possibilities of gene therapy, the specific identification
of the mutated nucleotides could lead to breakthrough studies on the complex
I protein. Once the etiology of this mysterious disease is found,
the cure is not far away.
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. If combined, the consideration of all four theories
presented above (free radicals, mysterious neuronal apoptosis, environmental
toxins, and genetic inheritance) could lead to even further advances in
the ongoing battle against Parkinson's disease. 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.
4. Novel therapeutic directions for Parkinson's disease
5. Freezing phenomenon in Parkinson disease
6. Parkinson's disease: drug therapy
8. Editorials from the Front Line
9. Familial Parkinson's Disease: A Clinical Genetic Analysis
10. Genetic Defect May Point to Heredity as a Source of Parkinson's Disease