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MSA AND PARKINSONíS DISEASE RESEARCH NEWSLETTER  (July 05)

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In this Research Newsletter, we will try to explain the importance of analyzing and studying the research that neuroscientists, epidemiologists and toxicologists have published, over the last few years, in relation to their discoveries on MSA and Parkinsonís disease.

Those who read already our newsletter and attached printed information and contacted us, were able to enlighten their knowledge about the etiology of PD and MSA. Some doctors were able to advise their patients about subjects they were not aware before. We received serum samples from their patients, allowing us to determine chemicals and substances suspicious of causing neurological damage.

A large number of caregivers and family members also asked us many questions. Many of those who followed our advice, were soon able to report rapid improvements.

At the end of this research newsletter, we have included a list of selected abstracts from references in relation to characterized  chemicals causing MSA and Parkinsonís disease.

It is important to understand that many of those chemicals, do not affect negatively, every person using them, or exposed to them.

From a group of 1000 people, exposed to those chemicals, less than 10-% will develop some form of neurological damage. This can be caused because of an inability to metabolize or eliminate a specific family of chemical compounds. If these substances remain in the circulatory system for longer than a few hours, this person might suffer some form of neuronal damage.

It is not possible to avoid contact with all those chemicals. Many are useful in the control of detrimental crop pests and others will prevent contamination of drinking water, leading to bacterial diseases in children.

The responsibility therefore, falls on those, unable to catabolize those chemicals, to try as much as possible, to avoid direct contact with them
(Catabolism = The breaking down in the body of complex chemical compounds into simpler ones )

Toxicologists, are doctors who specialize in the field of environmental chemistry and the toxic effect some chemicals might induce in human populations.

With the help of environmental chemists and toxicologists, we have designed, Neurogenic Program Protocols, aiming to repair dopaminergic areas of the brain in MSA and Parkinsonís disease sufferers.

The Neurogenic Program is not easy to design and to follow. However, in many cases, it can give patients real results, unattainable elsewhere.

There are today, more than 2000 peer reviewed research medical publications about chemicals that have been identified as toxic causative agents of neurological damage, particularly in MSA and Parkinsonís disease.

There are also more than 20,000 unpublished reports and case studies from hospitals, clinics and private practices worldwide, reporting some form of neuronal damage caused by specific chemicals in food, in drinking water and in the environment.

Each one of the 2000 or more peer reviewed medical studies, involved the participation of hundreds of the world mots prestigious hospitals, scientists, doctors, nurses, statisticians and many other professionals. The cost of undertaking these studies on populations, sometimes as large as 100,000 people, has reached a cost of over 100 billion dollars over the years. This cost has been met mainly by: governmental agencies, world health organizations and private or public foundations.

The results, from these expensive studies, are available to everyone in the world. This has been paid by public funding, that is, funds that came from tax payers like you and everyone else. It is a shame then that this knowledge, to which you have contributed for its advance, will be disregarded, instead of utilized to help, to heal and to cure.

These studies have provided conclusive evidence about a large number of chemical substances now known to induce MSA and Parkinsonís disease.

For example, very many epidemiological studies have concluded that people using well water, with high pesticide content as their main drinking source, have a greater probability of developing Parkinsonís disease.

Our studies at the Nutritional Medicine Research UK, have identified a large number of additional chemicals that can cause neuronal damage and consequently trigger the development of Parkinsonís disease, Shy Drager Syndrome and MSA.

With normal ageing, dopaminergic neurons die at a rate of about 12% each decade after the age of 40. However, because of a chemical induced neuronal damage  the loss of up to 40% of the total dopaminergic pool of neurons, can occur in a few months.
If this event occurred in one person at the age of 40, then 10 years later, this person would have lost 50% of the total active dopaminergic neurons. (10% due to normal ageing and 40% due to chemically induced neuronal damage.) At the age of 50 the remaining number of dopaminergic neurons will be similar to the number he should have had at the age of 70.

When the loss of dopaminergic neurons exceeds 70%, Parkinsonís disease symptoms will start to appear

The continuous exposure to substances causing neuronal damage can produce an array of neurological symptoms, including autonomic failure, as can be observed in patients with Shy-Drager Syndrome. It is important to identify these substances in order that patients can avoid contact with them and thereby reduce their risk.

There are now hundreds of reported cases of MSA and PD patients who have, sometimes just by mere chance, avoided recent contact with a chemical responsible for causing neuronal damage in the past. If contact with the damaging agent occurred for a short period of time, patients may recover and become free of symptoms, soon after preventing exposure to the damaging agent.

If exposure to the damaging factor has been very strong or prolonged, soon after avoiding this exposure, the severity of the patientís symptoms will be at least reduced.

Our research project on MSA and PD etiology presently involves studying more than 2000 chemicals, in use today, known to cause some form of neuronal damage. Collaborative research using Nuclear Magnetic Resonance has given us a better understanding about the active chemical groups in each molecule. We are now able to identify some of these chemicals and trace elements in the serum samples of MSA and PD patients.

Progress is inevitably linked to new discoveries. When the innovation relates to new agricultural products like pesticides, this translates into improvements in farming methods. When it relates to new drugs, it means the alleviation of human diseases. However, not everyone tolerates and metabolizes these new substances in the same fashion. For the large majority, these innovative substances do not cause any problem. Just a small percentage of highly sensitive people, suffer neuronal damage and adverse reactions to them.

However, chemical and environmental damage, causing the early onset of PD, MSA and other neurodegenerative diseases, affects more than one million people in the USA. We would like to suggest that doctors and researchers, involved in the treatment of Parkinsonís disease and MSA, help to enrich the present knowledge on the etiology of these diseases, by testing serum samples, preparing questionnaires and statistical analysis based on the clinical and toxicology data available.

Unfortunately, there is little awareness about etiological factors. Patients would just like their doctors to prescribe drugs that will temporarily alleviate their symptoms. They donít really bother to ask their doctors to help find the causative factors of their disease. This is mainly because there is not enough public alertness about this important topic.

There is very little a neurologist can do to alleviate the symptoms of MSA, if the patient continues to be exposed to the specific chemical agent that is causing a continuous neuronal damage.

Some patients may develop adverse reactions to a drug that is essential to treat Parkinsonís disease. For example, continuous use of Permax (Pergolide) can produce heart and pulmonary fibrosis. This can cause at some stage, serious circulatory and respiratory problems and in some cases, pneumonia. But less than 5% of patients using Permax will develop these type of adverse symptoms,

In order that these sensitive patients can have an alternative medicinal substance to replace a PD drug when necessary, we have developed a line of purely organic vegetable extracts, rich in amino acids required for the synthesis of dopamine receptors. These organic vegetable extracts are able to alleviate many of the Parkinsonian symptoms in sensitive patients, without causing them any form of adverse reaction.

This line of organic vegetable extracts, is not a commercial line of products for large scale marketing, because to produced them, it is required an enormous amount of organic vegetable materials. Their use is limited to the few number of patients suffering from chemical sensitivities  to synthetic drugs and pesticides.

These organic vegetable extracts are used presently as part of our studies in the Neurogenic Dietary Program.

We sincerely believe that  for every human disease, there is, in nature, a plant, a tree, a vegetable or a fruit, able to give the precious substance to heal it.

The results so far with the use of the Neurogenic Program, in patients to whom we have managed to identify the chemical substances which caused neuronal damage, are very encouraging. Most of these patients are now  free of their previous MSA or Parkinsonís disease symptoms.

The Neurogenic Program establishes recommendations for each individual patient, based on the analysis of serum samples and its correlation with scientific data from the many peer reviewed published studies in biochemistry, environmental chemistry and epidemiological medicine.

Stage IV of our Neurogenic Dietary Program suggests that doctors, treating MSA and Parkinsonís disease, should advice patients suffering from a high sensitivities to synthetic chemicals,  to try to avoid exposure to chemicals with strong scientific evidence that its use or exposure, causes neuronal damage.

We are primarily interested to continue working with doctors that will help to undertake clinical studies, aiming to establish practical medicinal methods, to prevent damage and enhance regeneration of brain cells. We would like to substantiate the present evidence, that generation of new dopaminergic neurons can occur in Parkinsonís disease and MSA patients who follow the Neurogenic Dietary Program.

 GLOSSARY

Idiopathic: Denoting a disease of unknown cause.

Etiology: The science and study of the causes of disease and their mode of operation.

Epidemiology: The study of the distribution and determinants of health-related states or events in specified populations, and the application of this study to control of health problems.

Dopaminergic: Relating to nerve cells or fibers that employ dopamine as their neurotransmitter.

Nuclear Magnetic Resonance Spectrometry: A method to identify the structure of chemical compounds utilizing a constant in the equation relating the difference in energies between parallel and antiparallel spin alignments of atomic nuclei in a magnetic field.

Neurogenesis: Formation of new neurons in the nervous system.

SECTION IV.
ABSTRACTS FROM SELECTED REFERENCES

Abstract Conclusions are highlighted in bold characters.

Nature Neuroscience Volume 3 No 12 December 2000
Chronic systemic pesticide exposure reproduces features of Parkinson's disease
Ranjita Betarbet1, 2, Todd B. Sherer1, 2, Gillian MacKenzie1, Monica Garcia-Osuna1, Alexander V. Panov1 & J. Timothy Greenamyre1
1. Department of Neurology, Emory University, 1639 Pierce Drive, WMB 6000, Atlanta, Georgia 30322, USA
2. The first two authors contributed equally to this work

The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and -synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.
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Nature Neuroscience Volume 3 No 12 December 2000pp 1227 Ė 1228
A new link between pesticides and Parkinson's disease
Benoit I. Giasson & Virginia M.-Y. Lee
The authors are in the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Environmental factors are thought to be an important cause of Parkinson's disease. A new study shows that rats chronically treated with the mitochondrial inhibitor rotenone, a common pesticide, develop neuropathological and behavioral symptoms of Parkinsonism.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, affecting almost 1% of the population over 65. Although the symptoms and neuropathology of PD have been well characterized, the underlying mechanisms and causes of the disease are still not clear. In this issue, Betarbet et al.1 report that chronic administration of rotenone, a widely used pesticide, can induce the major features of PD in rats. This remarkable observation not only provides a new animal model for the study of PD, but will also reinvigorate interest in the possible role of exposure to pesticides and other toxins as a cause of human neurodegenerative disease.
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Clinical Autonomic Research 1, 9‑-13 (1991)
Environmental occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation
Linda E. Neel CA, MSW, Manuel R. Gomez2, MS, James Dambrosia3, PhD, Sherri Bale,4 PhD, Roswell Eldridge, MD and Ronald J. Polinsky, MD
Family Studies Section, Environmental Epidemiology Branch, National Cancer Institute; Mathematical Statistics Section, and MCI Neurogenetics Studies Unit, Neuroepiclemiology Branch, National Institute of Neurological Disorders and Stroke; 'Occupational Studies Section, Environmental Epidemiological Branch, National Cancer Institute; Clinical Neuropharmacology Section, Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke; National Institutes of Health, Bethesda, MD 20892, USA.

We studied 60 patients with multiple system atrophy and autonomic failure and 60 control subjects matched for age, sex and race. Their psychosocial history, pedigree and occupation were obtained by personal interview. An inventory of autonomic and neurologic symptoms was obtained from 148 first‑-degree relatives of the patients and 80 controls by a self‑-administered questionnaire. Patients with multiple system atrophy had significantly more potential exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, and pesticides than the control population. The potential exposures were determined in most subjects by their reported usual occupation. Clinical symptoms of multiple system atrophy were reported by a significantly larger group of patients' relatives than controls. These findings are possibly consistent with the hypothesis that multiple system atrophy develops as a result of a genetically determined selective vulnerability in the nervous system. Specific neuronal systems may become targets for environmental insults or toxins, and the disease state may occur when ageing neuronal systems can no longer sustain functional capacity. This preliminary study supports the need to further explore possible environmental, occupational, and familial contributions to the aetiology of multiple system atrophy.


Archives of Neurology Jan, 1999 56(1): 90-4.;
Multiple System Atrophy The Putative Causative Role of Environmental Toxins
HANNA, PHILIP A.; JANKOVIC, JOSEPH; KIRKPATRICK, JOEL B.
Department of Neurology, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas. 77030, USA
.

Background: Whereas a number of studies have investigated the putative role of environmental toxins in the pathogenesis of idiopathic Parkinson disease, the possibility of such a role in multiple system atrophy has received little attention. Design and Setting: Review of records of patients examined in the Parkinson's Disease Center and Movement Disorder Clinic, Baylor College of Medicine, Houston, From July 1, 1977, to February 4, 1998. Patients: We reviewed 100 consecutive medical records of patients who satisfied the diagnostic criteria for multiple system atrophy formulated by the Consensus Committee of the American Autonomic Society and
the American Academy of Neurology. Intervention: The type and amount of toxin exposure were verified by history and examination of records whenever possible. Severity of parkinsonism was assessed by clinical rating scales. Main Outcome Measure: Development of multiple system atrophy after environmental toxin exposure. Results: Eleven patients had a notable history of heavy exposure to environmental toxins. One patient with multiple system atrophy confirmed by postmortem evaluation was exposed to high concentrations of malathion, diazinon, and formaldehyde, while the other patients with multiple system atrophy had well-documented high exposures to agents including n-hexane, benzene, methyl isobutyl ketone, and pesticides. The case studied pathologically demonstrated extensive
advanced glial changes, including glial cytoplasmic inclusions in deep cerebellar white matter, brainstem, cortex (superior frontal, insula) and putamen, with notable cell loss and depigmentation of the substantia nigra and locus ceruleus. Conclusion: While many studies report a possible role of environmental toxins in Parkinson disease, such a role is even more likely in multiple system atrophy, as this is a sporadic disease.

Neurology. 1993 Jun; 43(6): 1150-8.
Environmental antecedents of young-onset Parkinson's disease.
Butterfield PG, Valanis BG, Spencer PS, Lindeman CA, Nutt JG.
Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland 97201.

We conducted an exploratory study of young-onset Parkinson's disease (YOPD) to examine occupational and environmental factors associated with disease risk. This case-control study included 63 YOPD patients (diagnosis on or before age 50); controls (n = 68) were diagnosed with rheumatoid arthritis. After controlling for the variables of race, educational level, sex, age, age at diagnosis, and family history of Parkinson's disease (PD), PD was positively associated with insecticide exposure (OR = 5.75, p < 0.001), past residency in a fumigated house (OR = 5.25, p = 0.046), herbicide exposure (OR = 3.22, p = 0.033), rural residency at time of diagnosis (OR = 2.72, p = 0.027), and nuts and seed eating 10 years before diagnosis (OR = 1.49, p = 0.021). PD was inversely associated with cigarette smoking at 5 years (OR = 0.50, p = 0.027), 10 years (OR = 0.43, p = 0.012), and 15 years (OR = 0.37, p = 0.005) before diagnosis, farm residency (OR = 0.38, p = 0.018), and exposure to dimethyl sulfoxide (OR = 0.10, p < 0.001). These findings are consistent with hypotheses linking PD to exposure to pesticide agents.


Neurology. 1998 May; 50(5): 1346-50.
The Risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living.
Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ.
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.

We assessed exposure to pesticides, farming, well water use, and rural living as risk factors for Parkinson's disease (PD) in a population-based case-control study consisting of men and women > or = 50 years of age who had primary medical care at Henry Ford Health System in metropolitan Detroit. Enrolled PD patients (n = 144) and control subjects (n = 464) were frequency-matched for age, race, and sex. When adjusted for these variables and smoking status, there was a significant association of occupational exposure to herbicides (odds ratio [OR], 4.10; 95% CI, 1.37, 12.24) and insecticides (OR, 3.55; 95% CI, 1.75, 7.18) with PD, but no relation was found with fungicide exposure. Farming as an occupation was significantly associated with PD (OR, 2.79; 95% CI, 1.03, 7.55), but there was no increased risk of the disease with rural or farm residence or well water use. The association of occupational exposure to herbicides or insecticides with PD remained after adjustment for farming. The association of farming with PD was maintained after adjustment for occupational herbicide exposure and was of borderline significance after adjustment for occupational insecticide exposure. These results suggest that PD is associated with occupational exposure to herbicides and insecticides and to farming and that the risk of farming cannot be accounted for by pesticide exposure alone.


Neuroepidemiology. 2003 Sep-Oct; 22(5): 305-10.
Association between Parkinson's disease and exposure to pesticides in southwestern France.
Baldi I, Cantagrel A, Lebailly P, Tison F, Dubroca B, Chrysostome V, Dartigues JF, Brochard P.
Laboratoire Sante Travail Environnement, Institut de Sante Publique d'Epidemiologie et de Developpement, 146 rue Leo Saignat, FR-33076 Bordeaux Cedex, France.

A case-control study was performed in southwestern France in order to assess the relationship between pesticide exposure and Parkinson's disease (PD) in the elderly. During the period from 1997 to 1999, 84 cases were recruited together with 252 population-based controls. Experts in occupational health reviewed job codes and provided pesticide exposure levels, making it possible to calculate cumulated exposure lifelong for individuals. Environmental pesticide exposure was considered in relation to the place of residence. A positive association was found with occupational pesticide exposure (odds ratio = 2.2, 95% confidence interval 1.1-4.3) in conditional logistic multiple regression analysis taking into account age, sex, educational level and smoking; however, no clear dose relationship was found. Our results support the hypothesis of an association between occupational pesticide exposure and PD and point to the need to investigate the role of fungicides, for which toxicological hypotheses exist.


Neurology. 1993 Sep; 43(9): 1693-7.
Risk factors for Parkinson's disease.
Hubble JP, Cao T, Hassanein RE, Neuberger JS, Koller WC.
Department of Neurology, University of Kansas Medical Center, Kansas City 66160-7314.

Parkinson's disease (PD) has been associated with rural living, well-water consumption, and pesticide exposure; however, the individual risk contribution of these variables has not been established. We examined social and medical histories of predominantly rural populations to determine relative risk factors for PD. Patients and controls were surveyed regarding residency, occupation, medical history, and social and dietary habits. An initial multiple logistic regression model was confounded by excessive variable colinearity. Principal factor analysis yielded three factors: rural living (including years of rural residency and ground-water use), pesticide use, and male lifestyle (male gender, head trauma, male-dominated occupations). Other variables did not load in factor analysis and were entered separately, with the three factor scores, in a second multiple logistic regression model. Significant predictors of PD emerged (in order of strength): pesticide use, family history of neurologic disease, and history of depression. The predicted probability of PD was 92.3% (odds ratio = 12.0) with all three predictors positive. Pesticide use (distinguishable from rural living) can be considered a risk factor for the development of PD, with family history of neurologic disease and history of depression serving as weaker predictors of PD.


Neuropsiquiatr. 1999 Jun; 57(2B): 347-55.
Genetics, drugs and environmental factors in Parkinson's disease. A case-control study
Werneck AL, Alvarenga H.
Servico de Neurologia do Hospital Central do IASERJ, Rio de Janeiro, Brasil.

A case-control study of Parkinson's disease (PD) was conducted in the city of Rio de Janeiro based on the assumption that neurotoxins with secondary parkinsonian action may be related to the development of Parkinson's disease. Ninety-two subjects with PD and 110 controls were queried through a questionnaire in order to investigate possible risk factors for the disease. The following factors were studied: herbicides/pesticides, exposure to chemicals, ingestion of drugs with secondary PD effects, rural life, water well source, family history, cranial trauma and cigarette smoking. Study of mentioned factors was achieved through univariate, stratified and multivariate analyses. Univariate and multivariate analyses demonstrated that PD was positively associated with family history (OR = 14.5; CI = 2.98-91.38), with the use of drugs with secondary PD action (OR = 11.01; CI = 3.41-39.41) and with exposure to chemical agents (OR = 5.87; CI = 1.48-27.23). PD was found to be inversely associated with cigarette smoking (OR = 0.39; IC = 0.16-0.95). Stratified analysis only confirmed family history and drug use, besides demonstrating that cigarette consumption could be a protection factor, when aforementioned factors were involved. This study might be a warning as to the cares that need to be taken regarding drug use and occupational exposure to chemical agents, as both types of substances present secondary PD action.


Clin Neurol Neurosurg. 2002 Sep; 104(4): 328-33.
Environmental risk factors of young onset Parkinson's disease: a case-control study.
Tsai CH, Lo SK, See LC, Chen HZ, Chen RS, Weng YH, Chang FC, Lu CS.
Neuroscience Laboratory, Department of Neurology, China Medical College Hospital, 2, Yuh-Der road, 404, Taichung, Taiwan, ROC.

While the cause of Parkinson's disease (PD) remains unknown, recent evidence suggests certain environmental factors, such as well water drinking, herbicides and pesticides exposure, and neurotoxins, may trigger the chain of oxidative reactions culminating in the death of dopaminergic neurons in substantia nigra to cause parkinsonism. Most studies to date focused on PD with old age onset. However, there is a peculiar group of parkinsonian patients, the young onset Parkinson's disease (YOPD), in whom the age of onset is before 40. It is intriguing to know whether earlier exposure to the putative neurotoxin(s) may contribute to the earlier onset. We therefore conducted this case-control study in which 60 PD patients, 30 YOPD patients and the same number of age- and sex-matched young controls were included. Using logistic regression, we found well water drinking and head injury were risk factors for the development of YOPD. When YOPD patients were compared with PD, we found head injury and exercise were the significant predictors. Keeping all other variables constant, head injury was a risk factor and exercise appeared to be a protective factor. We conclude early exposure to well water drinking and head trauma may trigger and expedite the appearance of parkinsonian features, but such acceleration may be prevented through regular exercise.
 

Environ Res. 2001 Jun; 86(2): 122-7.
Environmental risk factors and Parkinson's disease: a metaanalysis.
Priyadarshi A, Khuder SA, Schaub EA, Priyadarshi SS.
Department of Public Health, Medical College of Ohio, Toledo, Ohio 43614-5809, USA.

The study aim was to examine the association between Parkinson's disease (PD) and exposure to environmental factors such as living in a rural area, well water use, farming, exposure to farm animals, or living on a farm, and pesticides. A series of metaanalyses of peer-reviewed studies were performed, using 16 studies for living in rural area, 18 studies for well water drinking, 11 studies for farming, and 14 studies for pesticides. Prior to the metaanalyses, all studies were reviewed and evaluated for heterogeneity and publication bias. Significant heterogeneity among studies was detected and combined odds ratio (OR) was calculated using the random and the fixed-effect models. The majority of the studies reported consistent elevation in the risk of PD with exposure to environmental factors such as rural living and farming. The combined OR for rural residence was 1.56 [95% confidence interval (95% CI) 1.18-2.07] for all the studies, and 2.17(95% CI 1.54-3.06) for studies performed in United States. The combined OR for well water use was 1.26 (95% CI 0.97-1.64) for all the studies, and 1.44(95% CI 0.92-2.24) for studies done in United States. The combined OR for farming, exposure to farm animals, or living on a farm was 1.42 (95% CI 1.05-1.91) for all studies, and 1.72(95% CI 1.20-2.46) for studies done in United States. The combined OR for pesticides exposure was 1.85(95% CI 1.31-2.60) for all studies, and 2.16(95% CI 1.95-2.39) for studies done in United States. Dose-response relationships could not be established due to the imprecise nature of the reported data. Our findings suggest that living in a rural area, drinking well water, farming, and exposure to pesticides may be a risk factor for developing PD. Copyright 2001 Academic Press.


Neurology. 1997 Jun; 48(6): 1583-8.
Environmental risk factors and Parkinson's disease: a case-control study in Taiwan.
Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, Chen RC.
Department of Neurology, National Taiwan University Hospital, Taipei.

To explore environmental risk factors for Parkinson's disease (PD) in Taiwan, we investigated 120 patients with PD and 240 hospital control subjects matched with patients on age (+/-2 years) and sex. Based on a structured open-ended questionnaire, we carried out standardized interviews to obtain history of exposure to environmental factors, including place of residence, source of drinking water, and environmental and occupational exposures to various agricultural chemicals. In the univariate analysis, the history of living in a rural environment, farming, use of herbicides/pesticides, and use of paraquat were associated with an increased PD risk in a dose-response relationship. After adjustment for multiple risk factors through conditional logistic regression, the biological gradient between PD and previous uses of herbicides/pesticides and paraquat remained significant. The PD risk was greater among subjects who had used paraquat and other herbicides/pesticides than those who had used herbicides/pesticides other than paraquat. There were no significant differences in occupational exposures to chemicals, heavy metals, and minerals between PD patients and matched control subjects. The duration of drinking well water and alcohol consumption was not significantly associated with PD. There was an inverse relationship between cigarette smoking and PD. Environmental factors, especially exposures to paraquat and herbicides/pesticides, may play important roles in the development of PD in Taiwan.

 

Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:742-749, 1999
Environmental, medical, and family history risk factors for Parkinson's disease: a New England-based case control study.
Taylor CA, Saint-Hilaire MH, Cupples LA, Thomas CA, Burchard AE, Feldman RG, Myers RH.
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.

Controversy persists about the etiology of Parkinson's disease (PD). Pesticides, herbicides, well-water consumption, head injury, and a family history of PD have been reported as risk factors for PD. The purpose of this study was to (1) investigate the impact of environmental factors on PD risk (2) estimate the chronology, frequency, and duration of those exposures associated with PD; and (3) investigate the effects of family history on PD risk. One-hundred and forty PD cases were recruited from Boston University Medical Center. The control group was composed of 147 friends and in-laws of PD patients. Environmental, medical, and family history data were obtained by structured interview from each participant for events recalled prior to PD onset for cases, or corresponding censoring age for controls (mean age = 56 years of age for each group). A traditional stratified analysis, adjusting for birth cohort and sex, was employed. Four factors were associated with increased risk for PD: (1) head injury (OR=6.23, confidence interval [CI]: 2.58-15.07); (2) family history of PD (OR=6.08, CI: 2.35-15. 58); (3) family history of tremor (OR=3.97, CI: 1.17-13.50); and (4) history of depression (OR=3.01, CI: 1.32-6.88). A mean latency of 36. 5 (SE=2.81) years passed between the age of first reported head injury and PD onset. A mean latency of 22 (SE=2.66) years passed between the onset of the first reported symptoms of depression and onset of PD. Years of education, smoking, and well-water intake were inversely associated with PD risk. PD was not associated with exposure to pesticides or herbicides. These findings support the role of both environmental and genetic factors in the etiology in PD. The results are consistent with a multifactorial model.. .
 

Acta Neurol Scand. 2002 Feb; 105(2): 77-82.
Familial and environmental risk factors in Parkinson's disease: a case-control study in north-east Italy.
Zorzon M, Capus L, Pellegrino A, Cazzato G, Zivadinov R.
Department of Clinical Medicine and Neurology, University of Trieste, Trieste, Italy.

BACKGROUND AND OBJECTIVE: The aetiology of Parkinson's disease remains unknown, although both genetic susceptibility and environmental factors are considered putative contributors to its origin. We performed a case-control study to investigate the association of familial and environmental risk factors with Parkinson's disease (PD). METHODS: We studied 136 patients with neurologist confirmed PD and 272 age- and sex-matched controls, affected by neurological diseases not related to PD. The risk of developing idiopathic PD associated with the following familial and environmental factors: positive family history of PD, positive family history of essential tremor (ET), age of mother at subject's birth, rural birth, rural living, well water use, farming as an occupation, exposure to pesticides, head tremor, exposure to general anaesthesia and to ionizing radiations, food restriction, concentration camp imprisonment and smoking has been assessed by using univariate and multivariate statistical techniques. RESULTS: In the conditional multiple logistic regression analysis, positive family history of PD (OR 41.7, 95% CI 12.2-142.5, P < 0.0001), positive family history of ET (OR 10.8, 95% CI 2.6-43.7, P < 0.0001), age of mother at subject's birth (OR 2.6, 95% CI 1.4-3.7, P=0.0013), exposure to general anaesthesia (OR 2.2, 95% CI 1.3-3.8, P=0.0024), farming as an occupation (OR 7.7, 95% CI 1.4-44.1, P=0.0212) and well water use (OR 2.0, 95% CI 1.1-3.6, P=0.0308) exhibited a significant positive association with PD, whereas smoking showed a trend toward an inverse relationship with PD (OR 0.7, 95% CI 0.4-1.1, P < 0.06). CONCLUSIONS: We conclude that both familial and environmental factors may contribute to PD aetiology.


Neuroepidemiology. 2000 Nov-Dec; 19(6): 333-7.
Parkinson's disease and environmental factors. Matched case-control study in the Limousin region, France.
Preux PM, Condet A, Anglade C, Druet-Cabanac M, Debrock C, Macharia W, Couratier P, Boutros-Toni F, Dumas M.
Biostatistics and Medical Informatics Department, Faculty of Medicine, Dupuytren University Hospital, Limoges, France.

The study included 140 patients with Parkinson's disease (PD) and 280 non-Parkinson age-matched controls to evaluate environmental risk factors associated with PD. The effect of exposure to environmental and dietary factors was determined using conditional logistic regression. This multivariate analysis showed that PD in first-degree relatives and tea drinking were the main risk factors for PD. Smoking appeared to be a protective factor. Further research is needed to validate that tea consumption increases the risk of PD.
 

Neurology. 1992 Jul; 42(7): 1328-35.
Parkinson's disease and exposure to agricultural work and pesticide chemicals.
Semchuk KM, Love EJ, Lee RG.
Department of Community Health Sciences, Faculty of Medicine, University of Calgary, AB, Canada.

This population-based case-control study of 130 Calgary residents with neurologist-confirmed idiopathic Parkinson's disease (PD) and 260 randomly selected age- and sex-matched community controls attempted to determine whether agricultural work or the occupational use of pesticide chemicals is associated with an increased risk for PD. We obtained by personal interviews lifetime occupational histories, including chemical exposure data, and analyzed the data using conditional logistic regression for matched sets. In the univariate analysis, a history of field crop farming, grain farming, herbicide use, or insecticide use resulted in a significantly increased crude estimate of the PD risk, and the data suggested a dose-response relation between the PD risk and the cumulative lifetime exposure to field crop farming and to grain farming. However, in the multivariate analysis, which controlled for potential confounding or interaction between the exposure variables, previous occupational herbicide use was consistently the only significant predictor of PD risk. These results support the hypothesis that the occupational use of herbicides is associated with an increased risk for PD.

Neurotoxicology. 2000 Aug; 21(4): 435-40.
 A meta-analysis of Parkinson's disease and exposure to pesticides.
Priyadarshi A, Khuder SA, Schaub EA, Shrivastava S.
Department of Public Health, Medical College of Ohio, Toledo, USA.

This study examined the association between Parkinson's disease (PD) and exposure to pesticides. A series of meta-analysis of peer-reviewed studies were performed, using 19 studies published between 1989 and 1999. Prior to the meta-analysis, all studies were reviewed and evaluated for heterogeneity and publication bias. Significant heterogeneity among studies was detected and combined odds ratio (OR) was calculated using the random effect model. The majority of the studies reported consistent elevation in the risk of PD with exposure to pesticides. The combined OR studies was 1.94 [95% confidence interval (95% CI) 1.49-2.53] for all the studies, and 2.15 (95% CI 1.14-4.05) for studies performed in United States. Although the risk of PD increased with increased duration of exposure to pesticides, no significant dose-response relation was established, and no specific type of pesticide was identified. Our findings suggest that exposure to pesticides may be a significant risk factor for developing PD.


Int J Epidemiol. 2000 Apr; 29(2): 323-9.
Parkinson's disease mortality and pesticide exposure in California 1984-1994.
Ritz B, Yu F.
Department of Epidemiology, Center for Occupational and Environmental Health, School of Public Health, UCLA, Los Angeles, CA 90095-1772,
USA.

BACKGROUND: In the last two decades reports from different countries emerged associating pesticide and herbicide use with Parkinson's disease (PD). California growers use approximately 250 million pounds of pesticides annually, about a quarter of all pesticides used in the US. METHODS: We employed a proportional odds mortality design to compare all cases of PD recorded as underlying (1984-1994) or associated causes (1984-1993) of death occurring in California with all deaths from ischaemic heart disease (ICD-9 410-414) during the same period. Based on pesticide use report data we classified California counties into several pesticide use categories. Agricultural census data allowed us to create measures of percentage of land per county treated with pesticides. Employing logistic regression models we estimated the effect of pesticide use controlling for age, gender, race, birthplace, year of deaths, and education. RESULTS: Mortality from PD as the underlying cause of death was higher in agricultural pesticide-use counties than in non-use counties. A dose response was observed for insecticide use per county land treated when using 1982 agricultural census data, but not for amounts of restricted pesticides used or length of residency in a country prior to death. CONCLUSIONS: Our data show an increased PD mortality in California counties using agricultural pesticides. Unless all of our measures of county pesticide use are surrogates for other risk factors more prevalent in pesticide use counties, it seems important to target this prevalent exposure in rural California in future studies that use improved case finding mechanisms and collect pesticide exposure data for individuals.


J Neurol Sci. 2004 Feb 15; 217(2): 169-74.
Multiple risk factors for Parkinson's disease.
Gorell JM, Peterson EL, Rybicki BA, Johnson CC.
Department of Neurology, Henry Ford Health Sciences Center, Henry Ford Health System, Detroit, MI, USA
OBJECTIVE: To determine the relative contribution of various risk factors to the development of Parkinson's disease (PD). METHODS: Ten variables that were independently associated with PD in a health system population-based case-control study of epidemiological risk factors for the disease were jointly assessed. Stepwise logistic regression, adjusted for sex, race and age was used to develop a multiple variate model that best predicted the presence of PD. The population attributable risk was estimated for each variable in the final model, as well as for all factors together. RESULTS: The 10 initial variables included >20 years occupational exposure to manganese or to copper, individually; >20 years joint occupational exposure to either lead and copper, copper and iron, or lead and iron; a positive family history of PD in first- or second-degree relatives; occupational exposure to insecticides or herbicides; occupational exposure to farming; and smoking. Logistic regression resulted in a final model that included >20 years joint occupational exposure to lead and copper (p=0.009; population attributable risk [PAR]=3.9%), occupational exposure to insecticides (p=0.002; PAR=8.1%), a positive family history of PD in first- and second-degree relatives (p=0.001; PAR=12.4%), and smoking </=30 pack-years or not smoking (p=0.005; PAR=41.4%). All four variables combined had a PAR=54.1%. CONCLUSIONS: Our final model of PD risk suggests that occupational, environmental lifestyle and, likely, genetic factors, individually and collectively, play a significant role in the etiology of the disease. Clearly, additional risk factors remain to be determined through future research.


Can J Neurol Sci. 2001 May; 28(2): 144-7.
A case-control study of Parkinson's disease in urban population of southern Israel.
Herishanu YO, Medvedovski M, Goldsmith JR, Kordysh E.
Department of Neurology, Goldman Faculty of Health Sciences, Ben Gurion University, Beer-Sheva, Israel.

BACKGROUND: In recent years, an increased prevalence of Parkinson's disease (PD) in southern Israel was observed. The aim of this study was to determine which exposures are associated with PD in the urban population of this region. METHODS: Ninety-three PD patients living in towns were compared to 93 age and sex matched controls. A previously validated questionnaire, including demographic data, education, data on exposures, previous diseases, family history and habits, was administered. RESULTS: In multivariate logistic regression analysis, it was found that history of work in construction sites was the strongest predictor of PD risk, followed by exposure to pesticides. In contrast, there was a negative association with smoking and history of mechanical factory employment. When the same statistical analysis was limited to association of PD with smoking, pesticides and construction work, the latter was found to be the strongest risk factor. CONCLUSION: The risk factors for PD in this population are work on a construction site and exposure to pesticides.

Ann Neurol. 1994 Jul; 36(1): 100-3.
Parkinson's disease and brain levels of organochlorine pesticides.
Fleming L, Mann JB, Bean J, Briggle T, Sanchez-Ramos JR.
Department of Epidemiology and Public Health, University of Miami School of Medicine, FL 33136.

Epidemiological studies have suggested an etiologic relationship between pesticide exposure and Parkinson's disease (PD).

Organochlorine pesticides were assayed in postmortem brain samples from 20 PD, 7 Alzheimer's disease (AD), and 14 nonneurological control cases. The three groups were similar in age at death, sex, and demographic variables. Only two of 16 pesticide residues screened were detected. A long-lasting residue of DDT (pp-DDE) was found in the majority of cases of PD and AD, as well as in all the control cases; pp-DDT was significantly more likely to be found in AD controls than the PD cases (Fisher's exact two-tailed, p = 0.04). Dieldrin was detected in 6 of 20 PD brains, 1 of 7 AD, and in none of 14 control samples. Despite the relatively small number of brains assayed, the association between Dieldrin and the diagnosis of PD was highly significant (p = 0.03). Dieldrin, a lipid-soluble, long-lasting mitochondrial poison, should be investigated as a potential etiological agent of Parkinsonism.
 

Am J Epidemiol. 2003 Mar 1; 157(5): 409-14.
Neurodegenerative diseases and exposure to pesticides in the elderly.
Baldi I, Lebailly P, Mohammed-Brahim B, Letenneur L, Dartigues JF, Brochard P.
Laboratoire Sante Travail Environnement, Institut de Sante Publique d'Epidemiologie et de Developpement, Universite Victor Segalen Bordeaux 2, Bordeaux, France.

The authors investigated the hypothesis that exposure to pesticides could be related to central nervous system disorders in a prospective cohort study of 1,507 French elderly (1992-1998). Lower cognitive performance was observed in subjects who had been occupationally exposed to pesticides. In men, the relative risks of developing Parkinson's disease and Alzheimer's disease for occupational exposure assessed by a job exposure matrix were 5.63 (95% confidence interval: 1.47, 21.58) and 2.39 (95% confidence interval: 1.02, 5.63), respectively, after confounding factors were taken into account. No association was found with having a primary job in agriculture or with environmental pesticide exposure, nor was an association found in women. These results suggest the presence of neurologic impairments in elderly persons who were exposed occupationally to pesticides.


Can J Neurol Sci. 1995 Aug; 22(3): 232-4.
Environmental exposures in elderly Canadians with Parkinson's disease.
Chaturvedi S, Ostbye T, Stoessl AJ, Merskey H, Hachinski V.
Department of Clinical Neurological Sciences, Faculty of Medicine, University of Western Ontario, London, Canada.

BACKGROUND: Etiologic hypotheses for Parkinson's disease have implicated environmental factors, genetic factors, or a combination of the two. METHODS: Data from a survey of elderly Canadians (n = 10,263) with regard to their history of Parkinson's disease and previous environmental exposures were analyzed. Exposure to various environmental factors was compared between 87 patients with Parkinson's disease and 2070 elderly controls without Parkinson's disease. RESULTS: Exposure to plastic resins (OR (odd ratio) = 8.79), epoxy resins (OR = 6.94), glues (OR = 4.26), paints (OR = 3.84), and petroleum (OR = 2.30) products was significantly (p < 0.05) associated with Parkinson's disease. CONCLUSION: These substances deserve further exploration with respect to the possible development of parkinsonism.
 

Neurol Sci. 2001 Feb; 22(1): 97-9.
Epidemiology of multiple system atrophy. ESGAP Consortium. European Study Group on Atypical Parkinsonisms.
Vanacore N, Bonifati V, Fabbrini G, Colosimo C, De Michele G, Marconi R, Nicholl D, Locuratolo N, Talarico G, Romano S, Stocchi F, Bonuccelli U, De Mari M, Vieregge P, Meco G; European Study Group on Atypical Parkinsonism (ESGAP).
Department of Neurological Sciences, La Sapienza University, Rome, Italy
.

Multiple system atrophy (MSA) is a form of atypical parkinsonism with unknown etiology. The epidemiological studies conducted up to now on this disease are scarce. The incidence rate is about 0.6 cases per 100,000 persons per year. The prevalence rates show 4-5 cases per 100,000 persons. In Italy, about 4,900 prevalent cases have been estimated. The mean onset age is about 54 years; the median survival is 7-9 years. Only one case-control study has been performed on this disease. This study showed an increased risk of MSA associated with occupational exposure to organic solvents, plastic monomers and additives, pesticides and metals. Smoking habits seem to be less frequent in MSA cases (as in Parkinson's disease cases) than in healthy controls. Quinn's clinical criteria and those of the Consensus Conference promoted by the American Academy of Neurology are in fair agreement. We have performed a case-control study on 73 MSA cases, 146 hospital controls and 73 population controls.
 

J Neurol Neurosurg Psychiatry. 2002 Jun; 72(6): 798-800.
Sleep disorders and their determinants in multiple system atrophy.
Ghorayeb I, Yekhlef F, Chrysostome V, Balestre E, Bioulac B, Tison F.
Service d'Explorations Fonctionnelles du Systeme Nerveux, Clinique du Sommeil, Hopital Pellegrin, Place Amelie Raba-Leon, 33076 Bordeaux cedex, France.

OBJECTIVES: To evaluate the incidence, types, determinants, and consequences of sleep disorders in patients with multiple system atrophy (MSA) and determine whether their characteristics are similar to those of patients with Parkinson's disease (PD). METHODS: Information about sleep disorders was collected using a standardised questionnaire in an unselected group of 57 patients with MSA and in 62 patients with PD matched as a group for age, sex distribution, and disease duration. RESULTS: Seventy percent of patients with MSA complained of sleep disorders compared with 51% of patients with PD (p=0.03). The most commonly reported sleep disorders were sleep fragmentation (52.5%), vocalisation (60%), REM sleep behaviour disorder (47.5%), and nocturnal stridor (19%). Except for sleep fragmentation, the incidence of these disorders was significantly higher than in PD. Sleep problems tended to be associated with more severe motor symptoms, longer disease duration, depression, and longer duration of levodopa treatment. Half of patients with MSA with sleep disorders complained of daytime somnolence compared with 30% of patients with PD. Daytime somnolence was significantly associated with disease severity in MSA. CONCLUSION: This study shows that sleep disorders are more common in patients with MSA than in those with PD after the same duration of the disease, reflecting the more diffuse underlying pathological process in MSA.

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