Tumorigenesis In Parkinsons Disease
Objective/Rationale: The aim of the study is to investigate whether disease-causing genetic mutations in Parkinsons disease , particularly in the LRRK2 gene, also predispose individuals to different types of cancer. A link between Parkinsons disease and cancer is well described for several PD-associated genes, which may be either tumor-suppressor genes or tumor-causing genes. We propose a role for these mutations at the interface of rapid cell growth seen in cancer and cell death seen in Parkinsons disease.
Project Description:We will study the role of mutations, especially in LRRK2, in the formation of cancer by sequencing stored tumor cells of patients who have both Parkinsons disease and a history of cancer. We will perform comparative whole exome sequencing of tumor tissue and normal tissue in PD individuals, with emphasis on those with proven disease-causing mutations in order to compare the genes found in tumor tissue and normal tissue in the same individual. We will investigate the tumors of these individuals in great detail and map any mutations onto known biological pathways.
Anticipated Outcome: In addition to possibly shedding light on a disease pathway in Parkinsons disease, our study has the potential to open up completely novel strategies in targeting cell death in genetic forms of Parkinsons disease. In addition, findings may have implications for cancer treatment for these patients.
Symptoms And Diagnosis Of Parkinsons:
Lets take a further look at Parkinsons disease.
Did you know that certain medical procedures, such as bone marrow transplants, can cause Parkinsons symptoms? Head trauma, liver disease, tumors, lesions, and vascular disease are all direct causes of Parkinsons disease. Physicians tend to be careful when testing for Parkinsons. Several different tests need to be done:
- The first test will be a blood test. The purpose is to test for toxins that may be causing the symptoms of Parkinsons.
- Next, an MRI and CT scan will examine the entire body and look for any unusual obstructions or abnormal functions in the vascular region.
General Trends Between Pd And Common Cancers
Many epidemiological studies have indicated an inverse association between the risk of developing cancers and PD. In a meta-analysis of 29 studies by Bajaj et al. that included 107598 PD patients, the diagnosis of PD was associated with an overall 27 % decreased risk of all cancers included in the studies, and 31 % decreased risk after exclusion of melanoma and other skin tumors . Similarly, a recent 2014 meta-analysis by Catala-Lopez et al. found 17 % decreased risk of cancer in PD patients . The most widely reported reduced risks in PD patients are cancers of the prostate, lung, bladder, stomach, colorectal, blood, and uterus . While the lower risks of lung, bladder, and colorectal cancer, all smoking-related cancers, in PD patients are generally undisputed, stomach, leukemia, and uterine cancers fail to achieve significance in some studies for a clear inverse association.
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Drug Acts On Peoples Own Dopamine Process
Dr. Moussa says that the optimum dose for raising dopamine activity fits neatly with that for increasing the immune response.
Findings from earlier studies had already suggested, he remarks, that nilotinib appeared to spur both immune cells and brain cells to target the toxic alpha-synuclein, creating room for the healthy version to release the stored dopamine.
In addition, the team found that the dose of nilotinib that led to the most significant drop in blood levels of alpha-synuclein was 150 mg. Many people who have Parkinsons disease also have high blood levels of alpha-synuclein, which can be toxic.
Taken together, the results would suggest that nilotinib reduces toxic alpha-synuclein and inflammation in the brain, while at the same time preserving dopamine and the cells that produce it.
This is exciting because this kind of potential treatment for Parkinsons could increase use of a patients own dopamine instead of using or periodically increasing drugs that mimic dopamine.
Dr. Charbel Moussa
F Prognosis And Patient Counseling
Parkinsons is a progressive disease, although the rate and degree of progression is variable. Treatments such as levodopa that initially provide great improvement in motor skills, tend to lose their effect or longevity with time.
There are many Parkinsons support groups that patients and their families can benefit from. There is currently no genetic testing recommended for family members.
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Microglia: A Key Player
The brain is a common metastatic site for various types of cancers, especially lung cancer, which suggests failure of the immune defense in the brain environment. Microglia are believed to be the most important immune cells in the CNS. Interestingly, significant microglial activation has been observed in the vicinity of glioma tumor cells . In contrast to CNS inflammation, microglia associated with brain tumors do not seem to be active in inducing an effective antitumor response. The exact mechanism of this microglial inactivation remains unclear. There is evidence that some cytokines, such as IL-10 released from activated microglia, play important roles in local immunosuppression and progression of glioma, particularly promoting proliferation of tumor cells and their infiltration into surrounding normal brain tissue . Microglia also play an important role in phagocytosing tumor cells. During the past decades, more attention has been paid to the secretory property and chemotaxis of microglia, but microglial phagocytosis is not well-studied. The activity of phagocytosis can be modulated by cancer cells or the cancer environment. However, whether microglial phagocytosis functions to contribute to cancer or cancer defense still needs further investigation. A better understanding of microglia function is important for the development of immune-based treatment strategies against malignant brain tumors.
What Makes Them Different
MS and Parkinsonâs have different causes. They usually start to affect you at different ages, too.
MS often affects people between ages 20 and 50, but children get it, too. Parkinsonâs usually starts at age 60 or older, but some younger adults get it.
MS is an autoimmune disease. That means your bodyâs immune system goes haywire for some reason. It attacks and destroys myelin. As myelin breaks down, your nerves and nerve fibers get frayed.
In Parkinsonâs, certain brain cells start to die off. Your brain makes less and less of a chemical called dopamine that helps control your movement. As your levels dip, you lose more of this control.
Some genes may put you at risk for Parkinsonâs, especially as you age. Thereâs a small chance that people who are exposed to toxic chemicals like pesticides or weed killers can get it, too.
These symptoms are more common if you have MS. They not usually found in Parkinsonâs:
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Skin Cancer And Parkinsons Disease
Melanoma is a type of skin cancer consistently linked to PD. People who have had melanoma are at an increased risk for PD and people who have PD are at an increased risk of melanoma. Epidemiological studies have shown an increased risk of non-melanoma skin cancers in PD patients as well. Always be sure to talk to your doctor about any skin concerns.
Tips and Takeaways
- Non-motor symptoms such as sweating dysregulation and seborrheic dermatitis can be symptoms of PD
- Seborrheic dermatitis can usually be treated with lifestyle changes and over-the-counter creams. Sometimes prescription-strength creams are necessary
- Although many treatments have been developed for excessive sweating, they have not been tested specifically in people with PD. Discuss with your doctor to find out if any are a possibility for you.
- There is a link between PD and melanoma which you can read about in a prior blog.
- If any symptom is causing you discomfort or interfering with the quality of your daily life, be sure to discuss it with your doctor as it may be something that can be improved with treatment or modifications.
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Dr. Rebecca Gilbert
APDA Vice President and Chief Scientific Officer
Dysfunctional Protein Clearance Systems
There are two central protein clearance systems within cells responsible for the removal of dysfunctional proteins: the ubiquitin-proteasome system and the autophagy-lysosome pathway. The UPS is primarily responsible for breaking down abnormal proteins, and it does so by tagging them with ubiquitin and transporting them to the proteasome for degradation. The autophagy-lysosome pathway is divided into three constituents: macroautophagy, microautophagy, and chaperone-mediated autophagy . Briefly, in macroautophagy, intracellular components, including cytosolic proteins, are engulfed by the autophagosome, which then fuses with the lysosome, leading to the breakdown of its contents. On the other hand, in microautophagy, the lysosome alone engulfs and destroys cytoplasmic components. CMA is a more selective process, whereby molecular chaperones target specific proteins and transport them to the lysosome for degradation . Monomeric -synuclein is generally cleared by both the UPS and the autophagy-lysosome pathway , and damage in either of their machineries is implicated in the pathogenesis of PD by contributing to the accumulation of defective proteins, in particular soluble misfolded -synuclein .
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Ethnicity: Does Ethnicity Play A Role In The Relationship Between Parkinsons And Cancer
A study, conducted in 2015 in Taiwan among people of Chinese heritage, indicated an increased risk of cancer in people with PD. In order to explain why this study did not conform to prior results, the researchers suggested that the relationship between cancer and PD may differ in different ethnic populations. Particular genes influence cancer risk as well as PD risk, so it should come as no surprise that these factors may change in different populations. However, much more work must be done to confirm this result, and currently there are no changes to cancer screening for PD patients of particular ethnicities.
Sensitivity Analysis And Publication Bias
In sensitivity analysis, we recalculated the combined OR by omitting one study per iteration. Each study included in our meta-analysis showed no obvious influence on the effect size. Neither the funnel plot nor the publication bias was performed in any pooling analysis due to the included studies were less than ten.
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What About Cigarettes Parkinsons Smoking And Risk Of Cancer
As I mentioned in a previous blog, there is also an inverse relationship between cigarette smoking and PD. It is unclear whether that is because an ingredient of cigarette smoke protects smokers from PD, or because the lack of dopamine in people with PD make them more risk-averse as a group, and therefore less likely to smoke.
Regardless, because it is clear that smoking increases the risk of multiple types of cancer, any study that investigates the cancer rates of people with PD must always account for the fact that people with PD tend to smoke less than people without PD. The most recent study which analyzes the relationship between cancer risk and PD, as referenced above, takes great pains to remove this confounding factor in its statistical analysis. Even with taking differences in smoking rates into account, the conclusion of the study is that people who have had cancer are less likely to develop PD. It is also the case that rates of certain types of cancers that have not been linked to smoking are lower in people with PD. This fact supports the conclusion that the lower rates of smoking among PD patients is not the cause of the lower rates of cancer. Regardless of any study results, cigarette smoking is linked to numerous deadly diseases and must be avoided.
Parkinson’s Disease Linked To 16 Types Of Cancer: Study
A study conducted by the researchers in Taiwan linked Parkinson’s disease to 16 types of cancer in the first time research conducted to explain the association in the East Asian population. In the past, most of the epidemiological research on the connection between cancer and Parkinson’s has been conducted only on the Western population. Of the of 25 studies conducted in the past 50 years, most have proved people with Parkinson’s are at a reduced risk of developing cancer.
The research conducted in the past made it clear genetics plays an important role in the development of the disease. Researchers from the National Taiwan University College of Medicine in Taipei conducted their study in Taiwan to confirm the role of genetic background and other factors in development of disease.
The researchers used the data from Taiwan National Health Insurance Research Database to separate two groups of people — one with Parkinson’s and the other without. The researchers found Parkinson’s was not related to an elevated risk of developing thyroid, ovarian or breast cancer. However, the people with Parkinson’s were found at an increased the risk for 16 other forms of cancer, including lung, urinary tract and brain cancer, as well as leukemia and melanoma.
“Based on this nationwide study on the association between and cancer risk, we conclude that is a risk factor for most cancer in Taiwan, the .
The study has been published online in the journal JAMA Oncology.
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What Is Parkinsons Disease
Parkinsons disease is a progressive brain disorder that affects mobility and mental ability. If you or a loved one has been diagnosed with Parkinsons, you may be wondering about life expectancy.
According to some research, on average, people with Parkinsons can expect to live almost as long as those who dont have the condition.
B Appropriate Prophylaxis And Other Measures To Prevent Readmission
Ensure adequate nutrition and safe swallowing.
Fall prevention and physical therapy to strengthen the patient.
If the patient is to return home on discharge, make sure the primary caregiver has adequate support systems and community resources available to assist in care.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
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Literature Search And Data Extraction
This meta-analysis followed the MOOSE guidelines for reporting meta-analysis on observational studies and was registered on PROSPERO . We searched all published literature that reported PD association with cancer in MEDLINE via PubMed, Web of Science and EMBASE up to 1 March 2021. Search items related to PD, cancer and epidemiological studies were identified and modified for each database. We constrained our search in human studies and in the English language. Detailed search terms can be found in . Duplicates were matched based on author, year, and title in Endnote X9 and manually compared before removing.
What Should I Do If I Have A History Of Melanoma
Unlike melanoma, PD is an idiopathic disease, meaning that it occurs spontaneously, without a known cause. Therefore, people with melanoma cannot take steps to prevent PD. However, if have a history of melanoma, you can work with your healthcare provider to look for early symptoms of Parkinsons disease, as well as discuss your family history.
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What Imaging Studies Should Be Ordered To Help Establish The Diagnosis How Should The Results Be Interpreted
No radiographic studies are routinely used to diagnose Parkinsons disease. Brain imaging can identify strokes, tumors or other brain injury that could possibly lead to parkinsonism. When the clinical diagnosis is uncertain, some facilities offer dopamine transporter imaging studies , which can identify the presynaptic neuron degeneration seen in Parkinsons disease.
Study Selection And Data Extraction
The eligible studies were included in our meta-analysis on the basis of the following criteria: the study was a cohort and/or case-control study evaluating the relationship between PD and risk of prostate cancer an estimate of association with measures of variation was provided the study was published in English. When duplicated studies were identified, only the most informative study was included,,. Case reports and abstracts from meetings were excluded.
Data from each study were extracted independently by two authors according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and any disagreements were resolved by discussion or involvement of a third reviewer if necessary. The following data were extracted from each included study: the first author, population country, study design , publication year, patient information , ethnicity, follow-up time in years and outcome of interest. The Newcastle-Ottawa scale was used to assess the quality of the included studies. In addition, studies with NOS scores > 6 were considered high-quality studies .
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What The Team Did
The team at the Oxford Parkinson’s Disease Centre used cutting-edge stem cell techniques to grow brain cells from skin cell samples donated by people with a rare genetic form of Parkinson’s, and from healthy people without the condition.
The team followed the progression of the condition in brain cells made from the patients’ stem cells and saw that a number of important genes became inactive when problems first started to occur inside the Parkinson’s-inflicted cells.
The ‘switching off’ of these genes early in the process brought the condition on later.
Professor Caleb Webber, who co-led the study, says:
“This is the first time researchers have followed the progression of the condition over time in brain cells in the lab, something we simply cannot do in cells inside the living brain.”
Professor Richard Wade-Martins, who co-led the study, says:
“We think that switching off these genes in brain cells may play a vital role in the cell damage and death that occurs in Parkinson’s. Finding a way to ‘turn them back on’ with a drug could be a promising, unexplored way to develop new treatments.”
Diagnosis Of Parkinsons Disease
A number of disorders can cause symptoms similar to those of Parkinson’s disease. People with Parkinson’s-like symptoms that result from other causes are sometimes said to have parkinsonism. While these disorders initially may be misdiagnosed as Parkinson’s, certain medical tests, as well as response to drug treatment, may help to distinguish them from Parkinson’s. Since many other diseases have similar features but require different treatments, it is important to make an exact diagnosis as soon as possible.
There are currently no blood or laboratory tests to diagnose nongenetic cases of Parkinson’s disease. Diagnosis is based on a person’s medical history and a neurological examination. Improvement after initiating medication is another important hallmark of Parkinson’s disease.
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