What Are The Major Challenges In Searching For Environmental Causes Of Pd
The fact that late-onset sporadic PD takes decades to develop and the lack of understanding of this prolonged prodromal phase present a major challenge to understand environmental contributions to PD. In this disease development paradigm, causative exposures that initiate PD pathological process may have to occur and be documented decades before disease clinical diagnosis, which is often infeasible in epidemiological studies. Further, once neurodegeneration is initiated, many environmental and genetic factors may come into play to modify PD progression during the decades of prodromal disease development. As a consequence, even the most robust epidemiological findings, including those from longitudinal cohorts, are subject to alternative explanations. For instance, smokers have a robust and substantially lower risk for PD than non-smokers in all types of epidemiologic studies . While a causal interpretation that cigarette smoking reduces PD risk is appealing, alternative hypotheses such as reverse causation and confounding by personality and other unknown risk factors are equally possible . Similar analogies can be easily extended to most, if not all, of the presumed protective modifiable risk factors afore-mentioned.
Quick Summary If Youre In A Hurry
- Environmental factors such as exposure to certain pesticides and other chemicals, infection, and even brain injury have been found to slightly increase the risk of Parkinsons.
- Some individuals may be more or less susceptible to different risk factors.
- It is almost impossible to identify the exact cause of Parkinsons in most people.
Need To Know: Dr Ray Dorsey
Dr Ray Dorsey is David M Levy Professor of Neurology and Director at the Center for Health + Technology at the University of Rochester Medical Center, US, which has conducted more than 100 clinical trials including trials that led to the approval of four Parkinsons medications. He recently co-wrote the book,Ending Parkinsons Disease: A Prescription for Action.
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Other Relevant Environmental Exposures
Although not the focus of this article, the Braak hypothesis also provides strong rationales to systematically examine several other environmental exposures that have not been well studied in the context of PD development such as organic solvents , high temperature cooked meats and heterocyclic amines , respiratory or GI infections and inflammation , and the use of antibiotics and antiviral therapies .
Now Is A Major Opportunity To Move Forward
Although still somewhat controversial, the Braak hypothesis presents a unique hypothetical framework of PD development that may allow us to better conceptualize steps of PD prodromal development and environmental contributions. According to this hypothesis, PD Lewy pathology develops in six sequential stages, first in the olfactory bulb or enteric nerves , years if not decades, before spreading to the substantia nigra where dopaminergic neuron death occurs . In support of this hypothesis, recent clinical and epidemiological studies have clearly documented a wide range of nonmotor symptoms in PD patients, and some symptoms such as olfactory impairment , REM sleep behavior disorder , and constipation may have developed years, if not decades, prior to PD clinical diagnosis. While there are still substantial challenges to adequately define prodromal PD, by using these symptoms as noninvasive intermediate phenotypes, we may be able to bring new insights into this black-box of PD prodromal development by identifying factors that initiate PD pathogenesis, lead to these intermediate phenotypes, or modify progression to clinical PD . This framework may fundamentally improve understanding of PD prodromal development and contributions from environmental factors.
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Interplay Of Aging Genetics And Environment: What Animal Models Show
Aging is recognized to be the primary risk factor for PD with incidence rising exponentially with advancing age. Nevertheless, most elderly over 85years do not have PD. Familial PD due to monogenic causes account for about 5% of all PD but the majority of known mutations have incomplete and variable penetrance. It is hypothesized that genetic risk factors may render the individual more sensitive to the pathologic influence of other factors. For example, the cumulative risk of PD in carriers of LRRK2 p.G2019S, the most common LRRK2 mutation in PD, rises exponentially from the age of 50 onwards , suggesting that aging interacts with LRRK2 mutations to initiate disease. This observation is corroborated in a LRRK2 G2019S knock-in mouse model which showed dysfunctions in plasma membrane and vesicular DA transporters, and accumulation of serine129-phosphorylated -synuclein, the predominant form of -synuclein in Lewy bodies, in 12-month-old KI mice compared to age-matched wild-type mice. These changes were not present in young 3-month-old KI mice, suggesting a progressive response relying on the interaction of the mutation and aging . Similarly, another LRRK2 KI mouse model, LRRK2 R1441G, showed a progressive, age-dependent accumulation of oligomeric -synuclein in the striatum and cortex compared with age-matched WT mice this higher rate of oligomeric -synuclein accumulation in KI than WT mice was first apparent at 15months and became significant at 18months of age .
What Is Parkinsons Disease
Parkinsons disease is a motor system disorder resulting from the loss of dopamine-producing cells in the brain.1 PD mostly affects people over 60 years of age, but in rare cases can start as early as your 20s. The rate at which it progresses is different for different people, and early symptoms are difficult to catch.
PD affects your movements in a way that you cannot control it. It starts out with tremors, stiffness, and slow movements and gradually progresses into difficulty swallowing, speaking, sleeping, and even thinking. The most unfortunate part is that daily activities that youve been doing for years become not so doable, affecting relationships and your basic quality of life.
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Is Parkinsons Disease Hereditary
Hereditary diseases are passed from parents to their children, but cases of familial Parkinsons disease are very rare . The vast majority of Parkinsons cases are not transmissible.
Having Parkinsons disease does not affect your childrens risk of developing the disease. Similarly, your risk is not increased if your brother or sister has the disease. However, your risk may be increased if more than one person in your family has the disease.
Exposure to certain environmental factors or toxins may contribute to the development of Parkinsons disease.
The main environmental factors involved in Parkinsons disease are:
What Do We Know Now About Environmental Factors And Pd
In the past two decades, scientists have identified over a dozen environmental factors associated with the risk of developing PD, and for a majority, findings are reasonably consistent across studies . Examples include inverse associations with smoking , coffee drinking , vigorous exercise , ibuprofen use , and plasma urate , as well as positive associations with overall pesticide exposure , use of specific pesticides , and traumatic brain injury . For most of these associations, plausible biological hypotheses have been proposed. However, causal inference for these epidemiological findings has been very difficult. Apart from limited and often inconsistent experimental data, for most of these epidemiological observations, reverse causation is a viable potential explanation – that PD development prior to clinical diagnosis changes lifestyle and behavior rather than the other way around. Possible exceptions are the use of certain pesticides. For example, epidemiological findings on rotenone and paraquat are supported by strong experimental evidence, so much so that these chemicals are being used to generate rodent models for PD therapeutic research . Even for pesticides, there are many important questions unanswered. Therefore, despite its importance and a reasonable accumulation of literature, our understanding of environmental contributions to PD is still in its infancy.
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So Why Do Some People Get Parkinsons And Others Dont
Identifying risk factors for Parkinsons doesnt mean we know exactly what causes the condition. For environmental risk factors, some people whove been exposed to a potential risk factor for their whole lives may never develop Parkinsons, while others with seemingly low levels of exposure do.
The best explanation is that some individuals may be more or less susceptible to different risk factors. As weve discussed a bit above, this likely has a lot to do with individual variability in our genetic makeup the combination of many slight variations within our DNA may make us more or less susceptible to other risk factors.
Our susceptibility to environmental factors may also be influencedby how long and how often we are exposed, our diet and lifestyle, as well as age and gender. All of these different influences combine to make understanding individual risk very difficult. To complicate matters more, recent studies suggest that a person can be exposed to the risk factors years, or even decades, before Parkinsons symptoms arise, making them harder to identify.
Thats not to say that research into risk factors isnt important. Understanding what causes Parkinsons is the first step toward prevention.
With the number of people being diagnosed with Parkinsons increasing all the time, any initiatives to reduce the exposure to risk factors in our environment could help reduce the incidence of Parkinsons in the population.
We Know Age And Genetics Play A Role In Parkinsons But How Does The World We Live In Impact On Our Risk Of Developing The Condition
Parkinsons is a neurodegenerative condition affecting around 145,000 people in the UK. It develops when dopamine-producing cells in the brain stop working properly and, over time, are lost.
This much we know. But what we dont know is what actually causes Parkinsons. Its often referred to as idiopathic Parkinsons, which translates from the original Greek as a disease of its own kind the cause is unknown.
Age is the biggest risk factor most people who get Parkinsons are aged 50 or over. As we age, damaging molecules called free radicals build up inside our bodies, causing the cells to become stressed. Energy-producing mitochondria may stop working properly, damaged proteins may accumulate, and, over time the cells may die. Research has shown that dopamine-producing brain cells seem to be particularly vulnerable to these changes seen with ageing, increasing the risk of Parkinsons as we get older.
But, age isnt the only player at the table. People under the age of 50 can get Parkinsons too. This early onset Parkinsons is often linked to very rare changes in certain genes, such as those involved in removing damaged proteins and helping mitochondria to work properly.
In this blog, well specifically investigate environmental factors in more detail.
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Parkinson Disease Risks: Correctly Identifying Environmental Factors For A Chronic Disease
Center for Health + Technology and Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.
Address correspondence to: Karl Kieburtz, 265 Crittenden Boulevard, CU 420694, Rochester, New York 14642, USA. Phone: 585.275.8911 Email: .
Find articles byKieburtz, K.in:JCI |PubMed |
Center for Health + Technology and Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.
Address correspondence to: Karl Kieburtz, 265 Crittenden Boulevard, CU 420694, Rochester, New York 14642, USA. Phone: 585.275.8911 Email: .
J Clin Invest.
Genetic Profile Environmental Exposure And Their Interaction In Parkinsons Disease
Letizia Polito
1Golgi Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
2Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy
Academic Editor:
Abstract
1. Introduction
Exploring the contribution of environmental exposure markedly advanced our understanding of the mechanisms involved in the development of PD. Initial evidence came from findings that subjects exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine developed PD-like symptoms . Since then, environmental exposure to pesticides , polychlorinated biphenyls , organic solvents , metals , and air pollutants has been proposed to increase risk for PD. However, results concerning the contribution of environmental factors in PD are still inconsistent.
Altogether, although genes are likely to play a role, the vast majority of PD cases cannot be ascribed exclusively to genetic factors. PD is probably caused by a complex interplay of many genetic variants interacting with many nongenetic risk factors.
2. Monogenic Forms of PD
Recently, mutations in three novel genes, that is, the vacuolar protein sorting 35 homolog , eukaryotic translation initiation factor 4 gamma 1 , and dnaJ homolog subfamily C member 13 , were proposed to cause late onset autosomal dominant inheritance and need further replication to be confirmed .
3. Genetic Variants Associated with PD
4. Environment Factors Related to PD
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How Do Genetics Contribute To The Development Of Parkinsons Disease
Genes are like an instruction manual. They code the synthesis of molecules that make up the body. A change in these instructions can lead to different effects and potentially to diseases.
Some of these modifications or mutations have been identified in people living with Parkinsons disease. They increase the risk of developing the disease but are not common. Moreover, they do not always lead to the development of the disease.
Environmental Risk Factors For Parkinsons
When we talk about the environment, we mean the world around us, and the pathogens , toxic chemicals, and heavy metals that occupy it.
The idea that the environment could play a role in Parkinsons first arose from an unusual medical case in the early 1980s. A group of heroin users in California took drugs from a batch contaminated with a substance called MPTP. Almost overnight, they experienced a type of parkinsonism that could be treated with L-dopa. The case hit the headlines, and sparked an interest in how chemicals and other environmental exposures could play a role in Parkinsons.
Over the years, several more environmental factors have been suggested to influence the risk of developing Parkinsons. While some associations remain unproven, other factors have repeatedly been found to either increase or decrease risk.
1. Pesticide use
Over the years, studies have linked Parkinsons with rural living, farming, and well-water consumption. The common denominator in these studies is thought to be exposure to certain pesticides, including herbicides, insecticides, fungicides, and rodenticides.
2. Other chemicals
Trichloroethylene
Manganese
One study looking in welders in the US reported that exposure to manganese, found in welding fumes, increased the risk of developing manganism. And recent research suggests that this condition is caused by manganese triggering the misfolding of a protein in the brain cells, causing them to die.
3. Heavy metal exposure
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Environmental Factors In Parkinsons Disease
Here are environmental factors that may play a role in the development of Parkinsons disease:
Although environmental exposure to these and other toxins is of continued research interest, its hard to determine if any one substance is a culprit. Most often, individual cases of Parkinsons disease result from a complex interplay between genetics and environmental and other factors.
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Parkinson’s Disease Risk Factors
Although a primary cause for Parkinson’s disease is yet to be identified, a number of risk factors are clearly evident.
Advancing age– Although there is the occasional case of the disease being developed as a young adult, it generally manifests itself in the middle to late years of life. The risk continues to increase the older one gets. Some researchers assume that people with Parkinson’s have neural damage from genetic or environmental factors that get worse as they age.
Sex- Males are more likely to get Parkinson’s than females. Possible reasons for this may be that males have greater exposure to other risk factors such as toxin exposure or head trauma. It has been theorised that oestrogen may have neuro-protective effects. Or, in the case of genetic predisposition, a gene predisposing someone to Parkinson’s may be linked to the X chromosome.
Family history– Having one or more close relatives with the disease increases the likelihood that you will get it, but to a minimal degree. This lends support to the idea that there is a genetic link in developing Parkinson’s.
– Post menopausal who do not use hormone replacement therapy are at greater risk, as are those who have had hysterectomies.
Low levels of B vitamin folate– Researchers discovered that mice with a deficiency of this vitamin developed severe Parkinson’s symptoms, while those with normal levels did not.
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Environmental Risk Factors And Parkinson’s Disease: An Umbrella Review Of Meta
We assessed the strength of the evidence linking 75 environmental risk factors with Parkinson’s disease.
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Physical activity and constipation presented Class I evidence for an association.
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Head injury, anxiety or depression, beta-blockers, smoking, and serum uric acid presented Class II evidence for an association.
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The majority of the examined meta-analyses had large or very large heterogeneity, many had signals of bias, and confounding or reverse causation was a common explanation.
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Data from more prospective studies and investigation of sources of heterogeneity are needed to better understand the association between the risk factors and PD.
Theories About What Causes Parkinsons
The cause of Parkinsons disease is still unknown, although there is some evidence for the role of genetics, environmental factors, or a combination of both. It is also possible that there may be more than one cause of the disease. Scientists generally believe that both genetics and environment interact to cause Parkinsons disease in most people who have it.
Currently, there is an enormous amount of research directed at producing more answers about what causes Parkinsons disease and how it might be prevented or cured. When physicians diagnose Parkinsons, they often describe it as idiopathic . This simply means that the cause of the disease is not known.
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