An Old Disease Has A Younger Face

by Gary Vey

The old man, bent over, slow moving and with shaking hands is an archetypal image that we take for granted. The fact that such symptoms of old age are universally known suggests that they have been with humanity for a long time. In fact, several early sources, including an Egyptian papyrus, an Ayurvedic medical treatise and the Bible, describe these symptoms quite accurately. It is now thought that these descriptions were not merely the result of old age, but of an illness we now know as Parkinson's Disease, or PD.

In 1817, James Parkinson, an English physician, published An Essay on the Shaking Palsy and noted the progression of the disease in six patients. Recent studies, which included younger victims, suggested that the disease was not exclusive to advanced age and that other un-natural factors are involved.

More than a century and a half later, science has determined that Parkinson's Disease symptoms result from the inexplicable death of brain cells in the mid-brain. A structure called the substantia nigra, responsible for our positive reaction to rewards, certain addictive behaviors and body movements, utilizes a neuro transmitter called dopamine. In victims of PD the dopamine producing brain cells die off as the disease and symptoms progress.

Only a small percentage of PD victims appear to have a genetic pre-disposition but even these victims usually show symptoms in the latter years of life. What is new and disturbing are the growing numbers of Parkinson's diagnoses being made in younger people with particular socio-economic and job related profiles.

Having a diagnosis of Parkinson's Disease increases the likelihood of developing dementia and Alzheimer's Disease and is a significant factor in exploding medical and healthcare costs. Clearly, it is a problem that must be addressed.

Parkinson's Disease Not Just An "Old" Disease

Michael J Fox [above] was diagnosed with Parkinson's Disease in 1991 when he was only 30 years old, though he didn't break the news to the world until 1998. Most people aren't diagnosed with this debilitating disease until their 50s.

The late Palestinian leader, Yasser Arafat, suffered from PD as does rocker Ossie Osbourne. Osbourne initially thought his hand tremors were from years of drug abuse until he was recently diagnosed. Pope Paul VI also suffered from PD and, towards the end of his life, had great difficulty walking and talking. Adolph Hitler suffered from tremors which were originally believed to be the result of injuries suffered in an explosive assassination attempt. Records of his private physician, discovered after his death, confirmed the diagnosis of PD.

Presidential hopeful Hillary Clinton also suffered from PD and it is believed this caused her downfall spiral for the White House in 2016.

PD Now Affects Younger Victims

Whereas the typical Parkinson's patient is diagnosed in their mid-50s, most PD victims were much older. Early symptom of tremors and "clumsiness" began showing up much earlier in the latter part of the 20th Century. Statistical analyses showed that Parkinson's victims were primarily male, non-smokers and worked as farmers, ranchers or fishermen and were blue-collar workers. This suggested that something in the environment -- perhaps a toxin -- was involved. Although some women got the disease it was believed that they were also exposed to a toxin through gardening related activities. The focus soon turned to herbicides and pesticides, especially paraquat, the most widely used herbicide in the world.

Paraquat [1] was first synthesized in 1882 but it was not recognized as a strong herbicide until 1955. The chemical is a potent killer of all plant life upon contact. It is absorbed by the green tissue within hours of application and so resists being washed off by rain or irrigation. It functions by interfering with a plant's photosynthesis and is able to renew itself and persist for a long time.

Farmers used to plow and till the soil before planting seed to eliminate weeds that would compete with their crops. Spraying fields with paraquat effectively killed the weed and eliminated this time consuming routine. The paraquat, once in the soil, would deteriorate and pose little toxicity to the main crop. Because of this, it became the world's leading herbicide in the second half of the 20th Century.

Like DDT, applying toxic chemicals to crops was considered "safe" and companies making them fought their restricted use. Because the residual amounts of paraquat were small, it was largely ignored. No animals dropping dead from exposure to paraquat like they were with DDT. Scientists were reluctant to consider the long term affects, especially since the herbicide was so widely used around the globe.

Exposure to high levels of the industrial weed killer paraquat combined with a previous head injury have been identified as a serious combination risk factor increasing a person's chance of developing Parkinson's disease.

According to a report from the Canadian medical site, suffering a head injury and being exposed to paraquat tripled a person's chances of developing Parkinson's disease. Each of these factors can stand alone as one that can significantly increase a person's chance of developing Parkinson's disease but a new study appearing in the most recent edition of the journal Neurology found that both those risks combine to raise the chance of Parkinson's even more.

[source: November 2012]

Enter the hero: Michael J Fox

Best known for his role in the still popular cinematic series Back to the Future, Fox was the epitome of a youthful and successful actor. His boyish appearance and superb acting destined him for a successful lifetime career. Then, at age 30, he announced that he was diagnosed with Parkinson's Disease.

Notably shaking and having some problems with his speech, Fox soon became a symbol and brave spokesperson for a disease that most people knew little about. Fox used his influence and popularity to make the public demand more research into a disease that is affecting more and more young people.

In 2006, Fox and his foundation, together with the Kinetic Foundation, sponsored research at Harvard's School of Public Health and shed light on the significant link between PD and paraquat [source]. Although no causal relationship was established, the findings broke the ice and prompted scientists to conduct experiments with animals and tissue samples.

Pesticides and Parkinson's: Further Proof of a Link Uncovered

On Jan. 3, 2013, ScienceDaily reported that paraquat was not the only culprit linked to Parkinson's Disease. Other popular pesticides and herbicides were also to blame.

Neurologists at UCLA have found that a link exists between Parkinson's and paraquat, maneb and ziram -- common chemicals sprayed in California's Central Valley and elsewhere. These chemicals have been tied to increases in the disease, not only among farmworkers but in individuals who simply lived or worked near fields and likely inhaled drifting particles.

Now, UCLA researchers have discovered a link between Parkinson's and yet another pesticide, benomyl, whose toxicological effects still linger some 10 years after the chemical was banned by the U.S. Environmental Protection Agency.

Even more significantly, the research suggests that the damaging series of events set in motion by benomyl may also occur in people with Parkinson's disease who were never exposed to the pesticide, according to Jeff Bronstein, senior author of the study and a professor of neurology at UCLA, and his colleagues.

Benomyl exposure, they say, starts a cascade of cellular events that may lead to Parkinson's. The pesticide prevents an enzyme called ALDH (aldehyde dehydrogenase) from keeping a lid on DOPAL, a toxin that naturally occurs in the brain. When left unchecked by ALDH, DOPAL accumulates, damages neurons and increases an individual's risk of developing Parkinson's.

The investigators believe their findings concerning benomyl may be generalized to all Parkinson's patients. Developing new drugs to protect ALDH activity, they say, may eventually help slow the progression of the disease, whether or not an individual has been exposed to pesticides.

The research is published in the current online edition of Proceedings of the National Academy of Sciences (January 2013).

"While researchers have identified certain genetic variations that cause an inherited form of Parkinson's, only a small fraction of the disease can be blamed on genes."

As a result, environmental factors almost certainly play an important role in this disorder. Understanding the relevant mechanisms -- particularly what causes the selective loss of dopaminergic neurons -- may provide important clues to explain how the disease develops."

--Arthur G. Fitzmaurice, a postdoctoral scholar in Bronstein's laboratory

Benomyl [2] (also marketed as Benlate) is a fungicide introduced in 1968 by DuPont. It is a systemic benzimidazole fungicide that is selectively toxic to microorganisms and invertebrates, especially earthworms. Benomyl binds to microtubules, interfering with cell functions, such as meiosis and intracellular transportation. The selective toxicity of benomyl as a fungicide is possibly due to its heightened effect on fungal rather than mammalian microtubules.

Due to the development and worldwide prevalence of resistance of parasitic fungi to benomyl, it and similar pesticide compounds became largely ineffective. High legal costs associated with it caused DuPont to cease its production in 2001 after 33 years on the market, and voluntarily requested cancellation for its registration. However, as DuPont's patents expired long ago and in some countries benomyl's registration has not been revoked, other manufacturers still produce it.

Benomyl was widely used in the U.S. for three decades until toxicological evidence revealed it could potentially lead to liver tumors, brain malformations, reproductive effects and carcinogenesis. So much for it being "safe" for mammals! It was banned in 2001.

The UCLA researchers wanted to explore whether there was a relationship between benomyl and Parkinson's, which would demonstrate the possibility of long-lasting toxicological effects from pesticide use, even a decade after chronic exposure. But because a direct causal relationship between the pesticide and Parkinson's can't be established by testing humans, the investigators sought to determine if exposure in experimental models could duplicate some of the pathologic features of the disease.

They first tested the effects of benomyl in cell cultures and confirmed that the pesticide damaged or destroyed dopaminergic neurons -- the cells that produce dopamine.

Next, they tested the pesticide in a zebrafish model of the disease. This freshwater fish is commonly used in research because it is easy to manipulate genetically, it develops rapidly and it is transparent, making the observation and measurement of biological processes much easier.

By using a fluorescent dye and counting the neurons, the researchers discovered there was significant neuron loss in the fish -- but only to the dopaminergic neurons. The other neurons were left unaffected.

Until now, evidence had pointed to one particular culprit -- a protein called α-synuclein -- in the development of Parkinson's. This protein, common to all Parkinson's patients, is thought to create a pathway to the disease when it binds together in "clumps" and becomes toxic, killing the brain's neurons.

The identification of ALDH activity now gives researchers another target to focus on in trying to stop this disease.

"We've known that in animal models and cell cultures, agricultural pesticides trigger a neurodegenerative process that leads to Parkinson's. And epidemiologic studies have consistently shown the disease occurs at high rates among farmers and in rural populations. Our work reinforces the hypothesis that pesticides may be partially responsible, and the discovery of this new pathway may be a new avenue for developing therapeutic drugs."

--Bronstein, who directs the UCLA Movement Disorders Program.

Marijuana Smokers May Suffer

During the late 1970s (and again in 1988), a controversial program sponsored by the US government sprayed paraquat on cannabis fields in Mexico. Since much of this cannabis was subsequently smoked by Americans, the US government's "Paraquat Pot" program stirred much debate. Perhaps in an attempt to deter people from using cannabis, representatives of the program warned that spraying rendered the crop unsafe to smoke. But few smokers cared.

A 1995 study found that "no lung or other injury in cannabis users has ever been attributed to paraquat contamination". The US Government also didn't think paraquat was a matter of concern for pot smokers.

"... toxic effects caused by this mechanism have been either very rare or nonexistent. Most paraquat that contaminates cannabis is pyrolyzed during smoking to dipyridyl, which is a product of combustion of the leaf material itself (including cannabis) and presents little toxic hazard..."

United States Environmental Protection Agency Manual

Like Agent Orange and other chemicals that were deemed "safe" in the past, paraquat may yet show its darkest side when baby-boomers who smoked cannabis in their youth, often handling and rolling the tainted plant material, begin to see the effects of their paraquat exposure.

For me, personally, I certainly hope not.