The hunt for the causes of Parkinson’s Disease
Many diseases have a clear cut point of origin, but one of the more baffling features of Parkinson’s Disease is that it seems capable of being initiated in a host of different ways, yet all appear to produce a similar outcome. This page describes some of the studies on clusters of Parkinson's cases where clues to causes can be discerned. This is preceded by some general comments on some noteworthy characteristics of the disease.
- 1 The PD Conundrum
- 2 The Multiple Hits Hypothesis
- 3 Clusters
- 4 Further Reading
- 5 Related Pages
- 6 References
The PD Conundrum
Currently every attempt at a generalisation about the cause of the disease faces a contradiction, exception or counter-argument.
All diseases involve the destruction of or damage to cells. Cells may be ruptured by blows or pressure; they may be starved of nutrients or lose their energy supplies; they may be poisoned by toxins; they can self-destruct or malfunction through inherited defects; and they can be attacked by invaders such as bacteria, viruses or prions. All of these types of cause have been noted as contributing to the Parkinson’s condition, leading to speculation that it may be a collection of diseases which happen to produce common symptoms or alternatively one disease which requires a combination of initiating factors.
What seems beyond contention is that the disease is not contagious. There are however occasional cases where both a husband and wife have contracted the disease (termed Conjugal Parkinsonism), but more often than not they are attributed to both individuals having been exposed to one of the known toxic causal risks such as pesticides.
There is no clinical test for the disease: no biomarker. Diagnosis is usually made by observation of four signature symptoms:- muscular stiffness, slow movement (bradykinesia), imbalance and resting tremor. There are a host of other symptoms, which vary from patient to patient. As a consequence cases of misdiagnosis are not uncommon. Other cases remain undiagnosed such as those in the pre-symptomatic (prodromal) phase of the disease.
There is also clear statistical evidence that the risk of contracting the disease increases with age (although early onset cases are by no means unknown). It could be argued that Parkinson’s is a natural by-product of the aging process and if everyone lived long enough they would all eventually succumb to the condition. Animals do not get the disease naturally. Even chimpanzees, who share 98.5% of human DNA, are not susceptible to PD. This may be a pointer to a defect in the human genetic make-up or may simply reflect the extended life expectancy of humans.
Having Parkinson's Disease is rather like being in charge of a chemical factory where the clocks in each department run at different speeds. Without a clear insight into cause and its consequences there can be no effective preventative action for the condition or a treatment which reverses the symptoms permanently, and this leads to a position where the best that can be achieved is the repair of the resultant damage once it has occurred, and at worst the palliative treatment of individual symptoms. Disease symptoms may be attributed directly to a point of origin, for example nasal infection with a norovirus produces runny noses and sneezing. But in many cases the cause starts a chain reaction around the body and the most affected organs are remote from the seat of the problem. This could be the case with Parkinson’s.
The disease is most closely associated with movement disorders arising from a shortfall in the production of the neurotransmitter dopamine by a part of the brain called the substantia nigra.  Dopamine replacement therapy is therefore currently the most effective form of palliative treatment. This does address the movement problems but there are many other non-motor symptoms  such as impaired speech or disrupted sleep patterns, which are less responsive to this form of medication, leading to the supposition that many other organs are affected by the disease. Dopamine is produced in at least two other areas in the brain which seem to be unaffected by the disease.Dopamine#Functions in the brain
Cannon et al (2011)  sum up the difficulties in finding an environmental cause for PD.
>Given the amount of research that has been conducted, the general conclusion that can be drawn is that outside of a few rare cases, it is highly unlikely that exposure to a single agent accounts for a significant number of cases. Much more likely, multiple hits over time from numerous compounds, in association with a background of genetic risk factors, are responsible for most cases.
Numerous other classes of environmental agents have been linked to PD, including organochlorines, organophosphates, and carbamates. However, currently, there is limited epidemiological evidence and chronic animal-based, laboratory-based research is mostly lacking.
The Multiple Hits Hypothesis
Over the past 20+ years a wider view of PD has begun to emerge. No longer simply an unfortunate encounter between genetics and environment, PD reveals itself as a complex`interplay between a half-dozen body systems.
Where clusters of the occurrence of a disease can be identified, this may provide a pointer as to its cause. Priyadarshi et al (2001)  carried out a comprehensive review of previous epidemiological studies of the disease and found that there was clear evidence of increased risk associated with living in a rural area, farming, drinking well water and exposure to pesticides, fungicides and herbicides.
The Amish, USA
The Amish are a sub group within the Christian church. They originated in the German-speaking parts of Switzerland. Amish communities are found in Pennsylvania, Indiana and parts of Canada and in total number some 250,000 individuals. The rules of the church demand strict adherence and include prohibitions or limitations on the use of power-line electricity, telephones, and machinery such as cars, as well as regulations on clothing and behaviour. Amish members will not buy insurance, accept social security payments or perform military service. The Amish communities are tightly knit and marriage outside the community is discouraged.
The Amish are also noteworthy for having the world’s highest prevalence of Parkinson’s Disease. This is 5,700 cases per 100,000 of the population over 60, and is two to three times the average. This has been widely cited as circumstantial evidence that genetic factors may be at work. This hypothesis was evaluated by Racette et al(2009) .
They studied the pedigrees of a number of members of the Amish community with PD and found no evidence of a pattern of Mendelian heredity as a cause. The community is largely devoted to agriculture, which includes the spreading of modern pesticides by hand, and it seems possible that the prevalence of the disease is associated with pesticide toxicity.
As is so often the case with PD, contradictory evidence was not long in coming. Cummings et al (2011)  studied the genomes of members of the Amish community and found statistical evidence to support the hypothesis that abnormalities in chromosome 6 might be the cause of the cluster.
Brescia in Northern Italy also has a high prevalence of Parkinson’s Disease and in 2007 a total of 2,677 patients were identified in a population of 903,977 residents. Lucchini et al (2007)  evaluated these and could find no evidence for Mendelian succession. When the cases were plotted geographically the clusters could be seen to coincide with the zones of fallout of manganese dust particles from the local ferroalloy industrial sites. Manganese has been recorded at several previous sites as a toxic originator of PD.
Manganese inhibits tyrosine hydroxylation, which is essential for the formation of dopamine. It has previously been implicated in the onset of PD in conjunction with welding and mining processes.
Negative clusters are very hard to detect, but Mlanov et al (2000)  found that among gypsies in the Sofia region of Bulgaria the prevalence of Parkinson’s Disease was 16/100,000 (based on one case) compared with 137/100,000 for the rest of the Caucasian population. No hypothesis was advanced to explain this but the inference is that they form a racial sub-group and might be genetically protected from the disease.
Bombay, (Mumbai) India
Barucha et al (1988)  carried out a door-to-door survey of a community of 14,010 Parsis living in the Bombay area and registered 46 PD cases. The Parsis practice a form of Zoroastrian religion, for which one of the ceremonies involves getting children to inhale the fumes from burning the leaves of aspand plants (Esfand sventa) in order to rid them of the Evil Eye. A Shi'a tradition states that there is an angel in each of the plant's leaves and seeds. Its root drives away sorrow and magic, and the devil stays a distance of seventy houses away from homes in which it is kept. Shi'a sources tell of the benefits of ingesting aspand or its juice. For instance, drinking a bit of aspand juice every day for forty mornings brings about wisdom in addition to fortifying the imbiber against seventy varieties of diseases. In practice aspand smoke contains two alkaloids, harmine and harmaline. These are inhibitors of the enzyme Monoamine oxidase which forms part of the metabolic sequence in the neurological processing of dopamine in humans.
Cox et al (2003) have described the high incidence of amyotrophic lateral sclerosis/parkinsonism-dementia complex (AL-SPDC), a neurodegenerative disease which starts with Parkinsonian symptoms but rapidly progresses to dementia and death. It is found among the Chamorro people on the island with an occurrence of 50 – 100 times above normal. The research determined that this came about through a complex chain of circumstances.
The island is populated by cycad trees (Cycas micronesica), the fleshy seeds of which secrete a neurotoxin nonprotein amino acid beta-methylamino-l-alanine (BMAA). Flying foxes (Pteropus mariannus) eat the seeds and accumulate BMAA, which does not seem to harm them. The flying foxes in turn are prized as a delicacy by the Chamorro, who boil them in coconut cream and eat the whole animal at fiestas and ceremonies. The researchers successfully linked the neurotoxin to the disease.
As a postscriopt to this it should be noted that the Australian aborigines have developed a method of rendering the cycad fruit edible by a process of leaching out the toxins. 
The American Parkinson’s Disease Association has identified Nebraska as the US State with the highest prevalence of PD with 329.3 cases per 100,000 of the population. It is the only State to implement legislation to create a statutory register of cases. The State has intensive farming of cereal crops and the high prevalence is generally attributed to crop spraying with pesticides, fungicides and herbicides.
Willis et al (2010)  carried out a statistical survey of US Medicare beneficiaries aged 65 and older from the years 1995 and 2000–2005. Using over 450,000 Parkinson’s disease cases per year, they calculated PD prevalence and annual incidence by race, age, sex, and county.
Their findings showed that the incidence of the disease increased steadily with old age without reaching any plateau. They found that people of White ethnicity had a substantially greater risk of contracting the disease than Blacks and Asians, indicating that susceptibility was influenced by genetic factors. They also confirmed the existence of a PD belt in the Midwest and Northeast regions of the country suggesting that environmental factors (pesticides?) might be involved.
Fukushima et al (2011) recruited a cohort of PD patients and non-PD cases from an outpatients clinic in China and took blood and urine samples. They found that the serum iron, whole-blood manganese and urine iron and copper levels were significantly higher in the PD patients than in the controls. The correlation coefficient between serum and urine concentrations of iron in the PD patients was significant. The serum vitamin E/urine copper ratio was significantly lower in the PD patients than in the controls. Serum vitamin E was negatively correlated with serum copper and was positively correlated with urine copper in the PD patients. Serum vitamin B12 was positively correlated with serum zinc in the PD patients and was negatively correlated with urine zinc in the controls. Mineral intake from the local diet was thought to be a causative factor.
Chen et al (2009)  carried out a study of the prevalence rates of PD in the urban areas of Keelung City and compared these with the rural area of Ilan County, Taiwan. The results were similar to those obtained in Sicily, Rotterdam, and 3 communities in China. They found that the prevalence rates of PD in the urban area studied were twice as high as those in the rural area.
Faroe Islands & Greenland
Wermuth et al (1997)  studied the prevalence of PD in the Faroe Islands and found indications of a cluster of 102 patients with parkinsonism and 82 with PD versus the expected 53. Their conclusions state:-
The high prevalence may be due to early diagnosis and a higher ascertainment of cases with mild disease. However, a high incidence cannot be excluded.
A follow-up study (2004)  found a similar high prevalence among the Inuit of Greenland.
Sasco and Paffenbarger (1985)  conducted a survey of 50,002 men who attended Harvard College (Cambridge, MA) or the University of Pennsylvania (Philadelphia, PA) between 1916 and 1950 and who were followed into adulthood for morbidity and mortality data.
Cases of Parkinson's Disease were identified from responses to mailed questionnaires and death certificates through 1978.
They found that there was a statistically significant lower risk of incurring Parkinson’s Disease among men who had been infected with the measles virus during childhood. Their conclusions stated "These data may also suggest a truly protective effect of measles, compatible with some complex interaction between measles virus and the virus of the 1918 influenza epidemic."
This unexpected finding raises the intriguing possibility that measles vaccines could be 'tweaked' to prevent the onset of Parkinson's Disease.
Canada (British Columbia)
Allyson-Jones et al (2012) measured the incidence of PD among elderly Canadians in the province of British Columbia and their cause of death. Statistics were compiled for persons aged 65 and over for the years 1991/92 to 2000/2001
Over the nine year period, age standardized incidence for males ranged from 207 to 396 per 100,000 person-years and 127 to 259 per 100,000 person-years for females. Persons with PD were at a 43% greater risk of all-cause mortality and specifically, 51% greater risk of injury mortality.
The epidemiology of Parkinson's Disease Ben-Shlomo (1997)
Willis, Alison Wright; Evanoff, Bradley, A.; Lian, Min; Criswell, Susan R. and Racette. Brad A. (2010) Neuroepidemiology. 2010 April; 34(3): 143–151. Geographic and Ethnic Variation in Parkinson Disease: A Population-Based Study of US Medicare Beneficiaries
Ponce, F.A. and Lozano A.M. (2011) Mov. Disord. 26 (3) 380-390 The most cited works in Parkinson's disease.
Larsen, Hans R. (2011) International Health News Parkinson's Disease: Is Victory in Sight?
- Cannon, Jason R. and Greenamyre, Timothy J. (2011) Full Text Toxicological Sciences 124 (3): 225-250. The Role of Environmental Exposures in Neurodegeneration and Neurodegenerative Diseases http://toxsci.oxfordjournals.org/content/124/2/225.long
- Priyadarshi, A.; Khuder, S.A.; Schaub, F.A. and Priyadarshi, S.S. (2001) Abstract Environmental Research 86 (2): 122-127. Environmental risk factors and Parkinson’s disease: a metaanalysis http://www.ncbi.nlm.nih.gov/pubmed/11437458
- Racette, Brad A.; Good, Laura M.; Kissel, Abigail M.; Criwell, Susan R and perlmutter, Joel S. (2009) Abstract 33 (3): 225-230 A Population-Based Study of Parkinsonism in an Amish Community http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826445/
- Cummings, A.C.; Lee. S.L.; McCauley, J.L.;Jiang, L.; Cruck, a.; MFarland, L.L.; Gallins, P.J.; Frizzell, D.; Knebausch, C; Jackson, C.C.; Scot, W.K.; Pericak-Vance, A.a. and Ha\ines, J.L. (2011) AbstractAnnals of Human Genetics 75 (3):351-358. A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6 http://www.ncbi.nlm.nih.gov/pubmed/21488853
- Lucchini, R.G.; Albini, E.; Beneditti, L.; Borghese, S.; Coccoglia, R.; Malara, E.C.; Pannicello, G.; Gratini, S. and Ressola, S. (2007) Abstract American Journal of Industrial Medicine 50 (11):788-800. High prevalence of Parkinsonian disorders associated to manganese exposure in the vicinities of ferroalloy industries,http://www.ncbi.nlm.nih.gov/pubmed/17918215
- Milanov I.; Kmetski, T. S.; Lyons, K.E. and Keller, W.C. (2000) Abstract Neuroepidemiology 19(4): 206-209. Prevalence of Parkinson’s disease in Bulgarian Gypsies http://www.ncbi.nlm.nih.gov/pubmed/10859500
- Bharucha, N.E.; Barucha, E.F.; Barucha, A.e.; Bhise, A.W. and Schoenberg, B.S. (1988) Abstract Archives of Neurology 45 (12):1321-1323. Prevalence of Parkinson’s disease in the Parsi community of Bombay, India http://www.ncbi.nlm.nih.gov/pubmed/3264148
- Cox, Paul Alan; Banack, Sandra Anne and Murch, Susan J. (2003) Full TextProceedings of the National Academy of Sciences of the United States of America 100 (23): 13380-13383. Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam http://www.ncbi.nlm.nih.gov/pmc/articles/PMC263822/
- Processing cycad fruit. http://austhrutime.com/food_preparation_poison.htm
- Willis, Allison Wright; Evanoff, Bradley A.; Lian, Min; Creswell, Susan R. and Racette, Brad A. (2010) Full TextNeuroepidemiology 34 (3): 143-151. Geographic and ethnic variation in Parkinson disease: a population-based study of US Medicare beneficiaries http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865395/
- Fukushima, T.; Tan, X,; Luo, Y. and Kanda, H. (2011) Full Text Neuroepidemiology 36 (4): 240-244.> Serum, Vitamins and Heavy Metals in Blood and Urine, and the Correlations among Them in Parkinson’s Disease Patients in China, http://www.ncbi.nlm.nih.gov/pubmed/21677448
- Chen, C.C.;Chen, T.F.; Hwang, Y.C.; Wen, Y.R.; Chiu, Y.H.; Wu, C.Y.; Tai, J.J.; Che, T.H. and Liou, H.H. (2009) AbstractNeuroepidemiology 33 (4): 350-357 Different prevalence rates of Parkinson’s disease in urban and rural areas: a population-based study in Taiwan http://www.ncbi.nlm.nih.gov/pubmed/19887842
- Wemuth, L.; Joensen, P.; Bunger, N. and Jeune, B (1997) Abstract Neurology 49 (2) 426-43. High prevalence of Parkinson's disease in the Faroe Islands. http://www.ncbi.nlm.nih.gov/pubmed/9270572
- Wermuth, L.; Bünger, N.; von Weitzel-Mudersback P.; Pakkenberg, H. and Jeune, B (2004) AbstractNeurology 49 (2) 426-43. Clinical characteristics of Parkinson's disease among Inuit in Greenland and inhabitants of the Faroe Islands and Als (Denmark).http://www.ncbi.nlm.nih.gov/pubmed/15254942
- Sasco.A.J. and Paffenbarger, R.S. Jr. (1985) Abstract Am. J. Epidemiol. 122 (6):1017-10131. Measles infection and Parkinson’s Disease http://www.ncbi.nlm.nih.gov/pubmed/4061437
- Allyson Jones, C.; Wayne Martin, W. R.; Wieler, M.; King-Jesso, P. and Voaklander, D. C. (2012) Abstract Parkinsonism Relat. Disord. 18 (4) 327-31. Incidence and mortality of Parkinson's disease in older Canadians. http://www.ncbi.nlm.nih.gov/pubmed/22197034