Etiology Of Parkinsons Disease: Current Concepts
Numerous genetic and environmental factors have been associated with Parkinsons disease , which is thought to be caused by a complex interplay of multiple factors unique to an individual. In the past decade, the number of known genetic risk factors has greatly increased with 90 risk alleles now identified . However, these known loci account for only approximately 20%of PD risk , leaving a substantial proportion of PD unexplained on the bases of currently known genetic associations. There is an urgent need to identify the missing etiologic fraction, to develop preventive and therapeutic strategies.
There is consistent or mostly consistent evidence for several environmental associations with risk of PD and a large number of associations with less consistent evidence spanning multiple categories, including dietary factors, chemical exposures, physical and emotional trauma . One of the more controversial categories of risk factors is infection, bacterial or viral.
Quantitation Of Snpc Da Neuron Number And Microglial Number
After perfusion, brains were dissected from the calvaria, postfixed overnight, then dehydrated through graded ethanols, defatted in xylene, and embedded in the coronal plane in paraffin . Serial 10-m sections were cut and all sections mounted onto Superfrost-Plus slides . Every other slide was immunostained for tyrosine hydroxylase and ionized calcium-binding adapter molecule 1 to immunolabel microglia using a two-color diaminobenzidine protocol.
The total number of SNpc TH-positive DA neurons were estimated by model-based stereology using the physical disector . On average, 40 sections per SNpc were analyzed. We used n = 6 for each experimental group, and these included equal numbers of male and female animals. Based on historical data in our laboratory , the n = 6 in each group will allow us a power of 0.80 accepting a type I error of 0.05.
Microglia numbers were estimated using design-based stereology . Microglia were deemed as resting if they contained a small oval Iba-1positive cell body that averaged three microns or less in diameter with long, slender processes, and as activated when the cell body was increased in size compared with resting microglia and had an irregular shape with shorter and thickened processes.
Whats The Connection Between Parkinsons And Infections
Some severe viral and bacterial infections lead to encephalitis, which is a dangerous condition that causes inflammation in the brain. Encephalitis can cause Parkinson-like symptoms. This has led researchers to explore the connections between viral infections and Parkinsonism.
To date, this research has been limited. Its possible that infections play a role in the development of Parkinsons disease, but researchers have yet to find any clear connections.
Viruses being investigated include:
To be clear, getting one of these viruses does not mean that you will get Parkinsons disease. Researchers are trying to determine if infectious illnesses may change something in a persons body that makes them more vulnerable to the condition.
Researchers are trying to see if there are connections between illnesses in earlier life and increased risks for Parkinsons disease.
According to a 2019 review of studies , there is some evidence suggesting that:
- People who get the flu vaccination may be less likely to get Parkinsons disease than people who dont.
- People with higher levels of the herpes simplex virus in their bodies may have more severe Parkinsons disease symptoms.
- People with Parkinsons are more likely to have had the Epstein-Barr virus than the general population.
- People with a history of hepatitis C may be more likely to get Parkinsons disease than others.
Risk factors for Parkinsons disease include:
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Ecu Researchers Find Possible Link Between Covid
A team of scientists, led by researchers from East Carolina UniversitysBrody School of Medicine, have identified another problem stemming from COVID-19 infections the potential for greater risk of Parkinsons disease.
The ECU contingent of researchers Dr. Jeffrey Eells, Dr. Shaw Akula, Dr. Srinivas Sriramula and Dr. Dorcas ORourke were joined by Dr. Rich Smeyne from Thomas Jefferson University and Dr. Pete Schmidt from New York University in a study of how COVID-19 infections could increase the likelihood of developing Parkinsons disease.
Through studying pre-clinical models that had recovered from COVID-19 exposure, the research team determined that the subjects were more sensitive to the effects of a Parkinsons Disease-inducing toxin. The models that showed Parkinsons-like brain disruption were infected with COVID-19, but did not get noticeably ill, much in the way that most humans infected with COVID-19 may have felt sick but did not need to be hospitalized.
I think this model represents people that are more susceptible to the virus infections. The subjects that we used got infected, because they have antibodies to the virus, but they werent really sick, said Eells, an associate professor of anatomy and cell biology at Brody.
Eells and Kristen Armel, a second-year medical student from Raleigh, look at slides in a laboratory at the Brody School of Medicine.
Causes Of Parkinson’s Disease
Parkinson’s disease is caused by a loss of nerve cells in part of the brain called the substantia nigra. This leads to a reduction in a chemical called dopamine in the brain.
Dopamine plays a vital role in regulating the movement of the body. A reduction in dopamine is responsible for many of the symptoms of Parkinson’s disease.
Exactly what causes the loss of nerve cells is unclear. Most experts think that a combination of genetic and environmental factors is responsible.
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Innate Immunity In Pd: Microglia Activation
Microglial cells are the principal actors of innate immunity in the CNS responsible for the protection and restoration of neurons . They can be activated by various external or internal insults such as neuronal dysfunction, trauma or certain toxin. Also, a wide range of molecules including viral or bacterial proteins, -syn, cytokines and antibodies are able to induce the activation of microglia . Consequently, microglial cells produce different molecular mediators with chemotactic and immunomodulatory functions. One of them is tumor necrosis factor which in PD plays important roles contributing to the regulation of synaptic plasticity . PD brains are characterized by the presence of HLA-DR+ microglial cells and raised levels of CD68, an activation marker for microglia and macrophages, having a direct relation with -syn aggregations and the duration of disease . Moreover, an increased expression of MHC-II molecules in microglial cells has been observed in chronic neuroinflammation but not in the CNS of healthy subjects . Individuals with single nucleotide polymorphism at MCH-II locus are prone to develop PD, which indirectly proves the importance of adaptive immunity in these patients .
What Else Causes Parkinsons
- exposure to toxins
- post-infectious encephalitis
Although doctors do not know exactly what causes Parkinsons disease, they do have a good idea of whats happening inside the brain when someone has the condition.
A part of the brain called the basal ganglia houses neurons that produce dopamine. Dopamine is a neurotransmitter responsible for many functions in the body, like the smooth movement of muscles.
In people with Parkinsons disease, dopamine-producing neurons die or become impaired in their function. As a result, there is less dopamine available in the brain.
Another neurotransmitter called norepinephrine may also be affected in people with Parkinsons disease. This is a neurotransmitter that controls heart rate, blood pressure, and other bodily functions.
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Top Questions And Answers On Covid
Since the coronavirus pandemic is currently part of our daily lives, the Parkinsons Foundation is addressing the top questions about the virus and Parkinsons disease . On March 18, 2020 Michael S. Okun, MD, Parkinsons Foundation Medical Advisor, and Fred Southwick, MD, Infectious Disease Expert and Author, both from the University of Florida Health, a Parkinsons Foundation Center of Excellence, answered the top COVID-19 questions from our community. View the event recording now. Of course, our Helpline Specialists, 1-800-4PD-INFO, are here to assist you with any other questions that are not covered here.
FAQ on COVID-19 and PD:
Expert COVID-19 Prevention Advice for people with Parkinsons:
1. Wash your hands for 20 seconds frequently. Sing happy birthday twice while washing.2. Socially distance: stay home, limit visitors and cancel all group gatherings.3. Know that all people with Parkinsons are at higher risk.4. Minimize cabin fever anxiety. Call or Facetime family and friends often.5. Reschedule all non-urgent doctors and dentist appointments. If deemed necessary, ask if it can be performed over the phone or telemedicine.6. If you get sick call your doctors office before going so they can be ready to protect you and others.7. If you are considering bringing a loved one home from a nursing home, talk to the healthcare team first.8. Avoid flights and travel.9. If you have Parkinsons, get the pneumonia vaccine and flu shot.
3. Should I get the pneumonia vaccine?
Inflammatory Biomarkers In Pd Patients
The presentation of infectious biomarkers among PD patients with or without mortality is shown in Table 5. Serum C-reactive protein , bandemia, and lactate levels were good indications for prediction of 28-day in-hospital mortality of infected PD patients. On receiver operating characteristic curve analysis, CRP, bandemia, and lactate had areas under the curve of 0.648 , 0.656 , and 0.653 , respectively, with different enrolled case numbers.
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Financial Disclosures Of All Authors
Stock Ownership in medically related fields: None.
Intellectual Property Rights: None.
Consultancies: D.P.O.: Council member emeritus for Association for Assessment and Accreditation of Laboratory Animal Care International.
Expert Testimony: None.
Advisory Boards: R.J.S.: Chair of the Scientific Advisory Board of the Parkinson’s Foundation D.P.O.: North Carolina Association for Biomedical Research and Sylvan Heights Waterfowl Park S.M.A.: Scientific Reports.
Employment: R.J.S., D.C., and M.B.: Thomas Jefferson University J.B.E., S.M.A., S.S., D.P.O., and P.S.: East Carolina University.
No One Definitive Cause Of Parkinsons
There are no biomarkers or objective screening tests that indicate one has Parkinsons. That said, medical experts have shown that a constellation of factors are linked to it.
Parkinsons causes are likely a blend of genetics and environmental or other unknown factors. About 10 to 20 percent of Parkinsons disease cases are linked to a genetic cause, says Ted Dawson, M.D., Ph.D., director of the Institute for Cell Engineering at Johns Hopkins. The types are either autosomal dominant or autosomal recessive .
But that leaves the majority of Parkinsons cases as idiopathic, which means unknown. We think its probably a combination of environmental exposure to toxins or pesticides and your genetic makeup, says Dawson.
Age. The biggest risk factor for developing Parkinsons is advancing age. The average age of onset is 60.
Gender. Men are more likely to develop Parkinsons disease than women.
Genetics. Individuals with a parent or sibling who is affected have approximately two times the chance of developing Parkinsons. Theres been an enormous amount of new information about genetics and new genes identified over the past 10 or 15 years that have opened up a greater understanding of the disease, says Dawson.
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Q: Once I Am Vaccinated Can I Go Back To Doing Things As I Was Doing Them Before The Pandemic
A: For the Pfizer and Moderna vaccines, you are not adequately protected from COVID-19 until about 2-3 weeks after your second vaccine dose. For the Johnson & Johnson vaccine, adequate protection occurs by about 2-3 weeks after the one required dose. Protection may be lower for some of the new variants of COVID-19 that are emerging. Masks and social distancing therefore remain in place for fully-vaccinated people when they are in public for the foreseeable future. You should also continue to avoid medium and large sized in-person gatherings. However, you can feel comfortable that your chance of getting the virus decreases significantly after you are fully vaccinated. In addition, even those who do get the virus after vaccination tend to have a milder course, which is another reason to seek vaccination.
The CDC has put together some guidelines of public health recommendations for fully vaccinated people. These include the new guideline that fully vaccinated people can socialize with other fully vaccinated people indoors without wearing masks or socially distancing. In addition, a fully vaccinated person can visit with unvaccinated people from a single household who are at low risk for severe COVID-19 disease, indoors without wearing masks or socially distancing.
Evaluation Of Striatal Dopamine Terminals And Microglia Density
After perfusions, brains were postfixed overnight in fresh fixative, cryoprotected in 30% sucrose, and then cryosectioned at 30m with all sections collected in 1× phosphate-buffered saline . Free-floating sections were incubated for 30minutes in 3% H2O2, washed in PBS-0.1% bovine serum albumin , and incubated into a 4% goat or rabbit serum in PBS-1% BSA-0.1%Triton X-100 for 1 h, then incubated in primary antibody overnight at 4°C. Sections were then washed five times in PBS-0.1% BSA and placed into secondary antibody conjugated to horseradish peroxidase for 2 h. Sections were rinsed, incubated in 0.25X ImmPACT DAB solution for 4 minutes, washed and mounted on silanized slides, dehydrated with graded ethanols, defatted in xylene, and coverslipped using Permount. For quantification of DA terminals, images were scanned using the MoticEasyScan with the extended depth of focus mode. TH axon densities were calculated using ImageJ software .
The density of resting and activated microglia, determined using the same criteria as used in the SNpc, was made in the dorsolateral striatum. Density was determined in two sections spaced 100 microns apart. The contour of the dorsolateral striatum was outlined and using StereoInvestigator, the area was calculated. Activated and resting microglia within the contour were counted, and using the area measurement, an average density was determined.
Neurodegenerative Diseases And Systemic Inflammation
Schematic diagram showing the relationship between peripheral inflammation and neuronal loss in PD. Neurodegenerative diseases present microglial activation as the main hallmark, which can change its morphology from resting towards an activated round shape . The intermediate stage, primed microglia, describes the atypical microglial stage, which precedes a further neurotoxic microglial activation as a consequence of a secondary pro-inflammatory stimulus. This stimulus can come from the periphery, either through neural or humoral pathways. Activated microglia release pro-inflammatory cytokines which can act on neuronal integrity.
The CNS has been considered as immunologically privileged and protected by the blood brain barrier which prevents entry of pathogens and immune cells into the parenchyma. However, this statement has changed in the last few years, because the communication between central CNS and periphery is more fluid than previously considered. In many neurological disorders, the immune system plays an important role in the progression of these diseases. Indeed, BBB breakdown and inflammation appear to play a major role in the pathology of numerous neurodegenerative diseases compromising the vascular unit and inducing leukocyte migration within the brain parenchyma .
Molecular Mechanisms And Basic Science Evidence For The Role Of Infection In Pd
Much of the evidence associating PD with infections, whether viral or bacterial, is based on obser-vational studies demonstrating increased risk to develop the disease, rather than direct evidence of infection as a singular cause. In fact, due to the complexity and multifactorial etiology of PD, identifying a single point of initiation in human PD is often impossible. For this reason, and the impossibility of interventional studies in humans involving infectious agents, the use of preclinical animal models of PD may provide the clearest evidence for or against a role of infectious agents in the etiology of PD.
Mechanistically, what might be the link between the cells of the peripheral immune system and the innate immune system in the brain? One critical component functions through recognition of MHCII a key antigen presenting protein . MHCII is critical for the presentation of antigen to both T-cells as well as microglial cells situated in the CNS . In regard to microglia, it is interesting to note that the SNpc contains the highest microglia:neuron ratio in the brain perhaps leading to its particular sensitivity to inflammation .
These observations provide plausible mechanisms to explain infection as either a susceptibility or cau-sative factor for PD. The hypothesized process by which infectious agents increase susceptibility to PD is summarized in Fig. 1.
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Infection And Risk Of Parkinsons Disease
Article type: Review Article
Affiliations: Department of Neuroscience, Vickie and Jack Farber Institute of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA | Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK | Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, UK | Department of Neurology, Mayo Clinic, Rochester, Minnesota and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA | The Edmond J Safra Program in Parkinsons disease, Toronto Western Hospital and the University of Toronto, Toronto, Canada
Correspondence: Correspondence to: Connie Marras MD, PhD, 7-MCL 399 Bathurst St. Toronto, Ontario, M5T 2S8, Canada. Tel.: +1 416 603 6422 Fax: +1 416 603 5005 E-mail:.
Keywords: Parkinsons disease, infection, viruses, bacteria, etiology
Journal: Journal of Parkinson’s Disease, vol. 11, no. 1, pp. 31-43, 2021
Q: What Happens If I Get A Cough From Covid
A: You are correct that it is important to pay attention to possible medication interactions. Cough and cold medications containing dextromethorphan, pseudoephedrine, phenylephrine, and ephedrine need to be avoided only if you are on a monoamine oxidase inhibitor such as rasagiline, selegiline or safinamide. Be sure to check the product ingredients before purchasing, and if you are unsure ask your doctor or pharmacist to clarify which brands/medications should be avoided. If you are on an MAOI, any other cold medication without these ingredients is safe for you to take. If you are not taking an MAOI, any cold medication is suitable for you.
Here is the list of medications to avoid in PD.
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