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http://ehpnet1.niehs.nih.gov/docs/1996/104-3/forum.html#what's
The cause of Parkinson's disease has baffled doctors ever since this
chronic neurological syndrome was first described by James Parkinson in
1817. Now scientists may finally be closing in on the culprits. The
disease is likely to be caused by "some admixture of genetic
predisposition, aging, and exposure to environmental toxicants,"
says Doyle Graham, chair of the pathology department at Vanderbilt
University Medical Center in Nashville.
Sorting out multiple potential causal agents and the
interactions among them will never be easy. However, thanks to
increasingly sophisticated research techniques, it may now be possible.
A prime example of the kind of meticulously designed research needed for
this purpose is a case-control study currently being completed at Henry
Ford Health System in Detroit. "This is one of only two
population-based studies to date in Parkinson's epidemiology, and it's
the only one of which I'm aware in which an industrial hygienist's
assessment of exposures, based on detailed occupational histories, has
been used," says Jay M. Gorell, lead investigator and director of
the hospital's Parkinson's disease center.
The study, now in the final data analysis stage,
included 144 Parkinson's patients and 469 control subjects who were
matched for age, race, and sex. Preliminary analyses, based on all but
10 of the patients and all but six of the controls, suggest an increased
risk of Parkinson's disease associated with exposure to manganese,
copper, and lead, as well as exposure to herbicides and insecticides
used at work. However, it may take some combination of factors to
produce Parkinson's disease. "It's possible that an agent might act
in a cumulative way over time to partially disable a cell, but it might
take several agents together to cause the cell either to fail to
function or to die prematurely," says Gorell.
While some researchers are devoting their energies to
determining which environmental agents contribute to Parkinson's
disease, others are more concerned with discovering how they do
so. The spectrum of possibilities ranges "from the enhanced
metabolism of substances into their toxic form to the diminished
protection of cells from these kinds of toxic products," says
Graham. One hypothesis he is pursuing relates to the potential role of
transition metals, such as manganese. Manganese poisoning produces
symptoms similar to Parkinson's disease, although it affects a different
site in the brain. Graham and his colleague, Thomas Montino, are
currently studying the effect of transition metals on neuroglial cells
in tissue culture.
Graham and others believe that transition metals may
contribute to the oxidation of catecholamines, compounds that carry
signals between nerve cells. One way that catecholamines are destroyed
is by the action of the enzyme monoamine oxidase that results in the
production of hydrogen peroxide, a known toxic compound. Catecholamine
oxidation can also occur by metal-catalyzed processes that produce their
own toxic by-products. Of course, cells have to cope with such natural
toxins on a regular basis, so they develop the ability to protect
themselves from cellular damage with enzymes that destroy toxins.
However, if the rate of toxin production is increased or the ability of
a cell to protect itself is lessened, this could lead to cellular injury
over time.
As research presents new evidence for a link between
environmental agents and Parkinson's disease, still other scientists are
trying to understand how such factors may interact with a given
individual's genetic makeup. The most likely scenario seems to be that a
person can inherit a predisposition to develop the disease that is only
later activated by a toxic exposure. For example, "a person may
have a genetic defect in the body machinery that deals with a toxic
compound, but if that person doesn't ever come across this toxic agent,
he may never develop the disease," says Donato Di Monte, director
of biochemical toxicology at the Parkinson's Institute in Sunnyvale,
California.
One major obstacle to all Parkinson's research, however,
is the lack of an objective test to diagnose the condition. At present,
diagnosis is based on the clinical assessment of a given patient's
symptoms, a method that can be inaccurate. The often conflicting results
of many older Parkinson's studies may, in fact, be partly due to a lack
of standardization in diagnostic criteria. Di Monte is among the
scientists now searching for biological markers of Parkinson's disease,
in the hopes of one day developing a simple, reliable test for the
condition. Some of his work is aimed at studying the products of
oxidative metabolism in spinal fluid.
The picture of Parkinson's remains complicated. Says Di
Monte, "We have to start looking at the interactions between
environmental and genetic factors. And among the environmental factors,
we have to start looking at interactions between neurotoxins. Naturally,
we would like to have a simple experimental model, but unfortunately
that may not be feasible with Parkinson's disease."
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