Migraines, OCD, and Seasonal Allergies May be Risk Factors for Parkinson’s, Large Study Suggests

Parkinson's traits

Migraines, obsessive-compulsive disorder, and seasonal allergies seem to be associated with Parkinson’s disease and are likely to occur many years before the typical age of diagnosis, a large study has found.

Results of the study, “The Parkinson’s phenome—traits associated with Parkinson’s disease in a broadly phenotyped cohort,” were published in the journal npj Parkinson’s Disease.

Trying to identify the factors that influence whether a person will develop Parkinson’s disease is not a new idea. However, because Parkinson’s is a rare disease, such studies often don’t have enough participants to be sure that associations are real and not the result of chance.

To try to get around this problem, researchers behind a new study analyzed data from 13,546 Parkinson’s patients and more than one million control subjects to find traits associated with Parkinson’s development.

The team primarily used data from customers of 23andMe — a web-based company that provides genetic testing and analysis — who consented to be included in the study, and from surveys sent to and filled by various Parkinson’s patient groups.

After amassing the data, the researchers set about finding the factors — including family history, other diagnoses, environmental factors, personality traits, and medication usage — that were correlated with developing Parkinson’s.

The team analyzed 832 traits individually, since not every patient had data for every trait. This resulted in a list of a few hundred traits that showed some evidence of an association with Parkinson’s. The researchers then applied statistical tests and corrected for factors such as education and income, and ended up with 122 traits that were significantly associated with the disease, including some previously known factors. For example, people who consumed a lot of caffeine were less likely to have Parkinson’s, and those with the disease were more likely to report experiencing constipation.

The researchers also identified 42 traits that had not previously been associated with Parkinson’s. For example, those who could wiggle their ears or whistle were less likely to have the disease, whereas Parkinson’s patients were more likely to be afraid of heights, be farsighted, have seasonal allergies, and be married.

This large study was able to shed light on associations that had been suggested but for which there hadn’t been large enough sample sizes to draw a definitive connection. For example, the investigators found that those with obsessive-compulsive disorder (OCD) were more likely to develop Parkinson’s, supporting previous studies that were too small to achieve significance.

Although previous studies have yielded non-significant results due to their small sample sizes, “with 10,437 (Parkinson’s) cases in this particular regression, our study was well-powered to detect a positive association between (Parkinson’s) and OCD,” the researchers stated.

In addition, they found a significant association between Parkinson’s and migraines.

“We observed that migraine was positively associated with (Parkinson’s),” they said. “Only two cohort studies have previously been conducted, but both found that midlife migraine was associated with increased risk of (Parkinson’s disease) …. Since the average age of onset is typically much earlier for migraine than for (Parkinson’s), migraine may be a novel (Parkinson’s) risk factor.”

While previous studies have shown that Parkinson’s was positively associated with allergic rhinitis, but not asthma or hayfever, the current study found that it was also associated with allergies to plants and antibiotics, but not with allergies to food or animals.

“Understanding the biological differences between these different groups of allergies may allow us to hone in on specific immunological pathways that contribute to (Parkinson’s) risk,” the researchers said. “Seasonal allergies typically develop early in life, but further research is needed to determine whether having seasonal allergies is a risk factor for (Parkinson’s). If so, it may be possible to manipulate risk using immune-modulating drugs.”

The researchers noted that their study showed correlations, and not causation — that one thing does not necessarily cause another because the two are correlated. For example, people with Parkinson’s tend to report being more introverted, but it’s highly debatable whether the factors that make a person introverted also predispose them to Parkinson’s or if people with Parkinson’s are more likely to become introverted due to the difficulties of living with a neurodegenerative disease.

Similarly, marital status doesn’t seem likely to influence the development of Parkinson’s, although the researchers noted that spouses may notice sleep disturbances, which could increase the chances of people eventually getting diagnosed. At this point, however, these ideas are largely speculation.

Still, this study is not without value: “Now that we have identified phenotypes (traits) that are correlated with (Parkinson’s) it is also possible to test whether these phenotypes are causes or consequences of the disease,” the investigators wrote, adding that even in the absence of a known causal relationship, “phenotypes that are correlated with (Parkinson’s) can be used to predict (the disease) as long as the phenotype is enriched in (Parkinson’s disease) cases prior to diagnosis.”

In other words, having the data about factors that are associated with Parkinson’s can be a starting point for further research. It could be used to make predictions about Parkinson’s patients, particularly through the use of computer models and machine learning, which can interpret these massive datasets more efficiently than people.

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Genetic Variant Predetermines Risk of Cognitive Decline in Parkinson’s, Research Suggests

genetic variant

Researchers have found that Parkinson’s patients whose cognitive ability is intact, but who have a specific genetic variant, have significantly less gray matter in the regions of their brain that are related to dementia.

The study with that finding, “Reduced gray matter volume in cognitively preserved COMT 158Val/Val Parkinson’s disease patients and its association with cognitive decline,” was published in Brain Imaging and Behavior.

Several mutations in the COMT gene have been associated with the risk of developing Parkinson’s disease. This gene provides instructions for making catechol-O-methyltransferase (COMT), an enzyme that helps break down certain chemical messengers like dopamine.

The most common alteration in the DNA sequence that makes up the COMT gene is the Val158Met mutation in which a valine (Val) is replaced by a methionine (Met) at position 158. Val and Met are both amino acids, also known as the protein’s building blocks.

Every individual has two copies of each gene, one inherited from each parent. Therefore, a person can have two Val’s in the same position at both COMT gene copies (also known as the Val/Val genotype), a Val in one gene and a Met in the other (Val/Met genotype), or two Met’s (Met/Met genotype). Scientists use the word “genotype” to describe a person’s genetic constitution.

Changes in COMT’s molecular structure, lead to high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzymatic activity.

The Val158Met mutation in the COMT gene has been associated with an increased risk of cognitive decline in Parkinson’s disease, particularly in people with greater COMT activity. When this happens, there is too much neurotransmitter degradation, thus leading to reduced levels of dopamine and affecting basic brain functions such as motor coordination and memory.

Evidence suggests a correlation between cognitive impairment, one of Parkinson’s non-motor features, and reduced gray matter volume.

The brain is composed of gray and white matter. The first consists of cell bodies — the control center of neurons — while the latter is made up of nerve cell projections, known as axons or fibers, connecting distinct parts of gray matter.

A Spanish team of researchers used magnetic resonance imaging (MRI), a non-invasive imaging technology, to investigate a possible structural brain compromise in Parkinson’s patients with highly active COMT activity that could explain their increased risk for subsequent cognitive impairment.

The study included 120 newly diagnosed Parkinson’s patients with normal cognition (who were not previously treated for the disease) and 48 healthy controls from the Parkinson’s Progression Markers Initiative database.

Results showed that there was a widespread, significant reduction in cerebral gray matter volume in patients with the Val/Val genotype. They observed alterations in the fronto-subcortical and posterior-cortical brain regions, where motor and cognitive functions originate.

Gray matter volume at some of the identified regions was associated with cognitive decline in a four-year follow-up period, suggesting that gray matter volume reduction during the early stages of disease predisposes Val/Val patients to cognitive impairment.

Nonetheless, gray matter volume analysis at one-year follow-up was not increased in Val/Val subjects, in comparison to Val/Met and Met/Met participants, indicating a somewhat stable atrophy in the Val/Val subset and that those brain changes might already be present prior to diagnosis.

The team believes their research “sparks the need to further characterize the association between a modified COMT enzymatic effect and a structural brain compromise in the early stages of [Parkinson’s disease].”

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First-degree Relatives at Higher Risk of Parkinson’s, Other Neuropsychiatric Disorders, Study Finds

first-degree relatives risk

First-degree relatives of Parkinson’s patients are more likely to develop the disease and are at a higher risk for other neuropsychiatric disorders, a study shows.

The study, “Familial aggregation of Parkinson’s disease and coaggregation with neuropsychiatric diseases: a population-based cohort study,” was published in Clinical Epidemiology.

Most Parkinson’s cases are considered to be sporadic, but several studies have suggested that the disease results from a combination of genetic and environmental factors.

Several genes have been pinpointed as the cause of 6 to 7 percent of the clinical variability observed in Parkinson’s disease.

To better understand the impact of genetic and environmental factors on the development of Parkinson’s, researchers reviewed potential risk factors that could be linked to familial aggregation of the disease.

Clinical records of all individuals registered in the Taiwan National Health Insurance Research Database in 2015 were analyzed. Of the total registered population of 24,349,599 individuals, 112,037 were diagnosed with Parkinson’s disease.

This included 149,187 individuals who had a parent affected by Parkinson’s, 3,698 with an affected offspring, 3,495 with an affected sibling, and 15 individuals with an affected twin.

Researchers found that individuals who had a first-degree relative with Parkinson’s disease had a 1.69 times increased chance of also developing the disease. This risk was similar for both male and female relatives and was greater for twins, who were 63.12 times more likely to develop Parkinson’s.

The risk of developing Parkinson’s was 2.2 times higher for siblings, 1.86 times higher for offspring, 1.59 times higher for parents, and 1.46 times higher for spouses.

These results suggest that the clinical variability of Parkinson’s prevalence observed in the Taiwanese population is accounted for by genetic factors (heritability) at 11%, shared environmental factors at 9.1%, and non-shared environmental factors at 79.9%.

Additional analysis further showed that first-degree relatives of Parkinson’s patients are also at an increased risk for some other neuropsychiatric disorders than the general population. These include major depression, anxiety, multiple sclerosisAlzheimer’s disease, and amyotrophic lateral sclerosis, among others.

Researchers believe that Parkinson’s disease “should be considered an age-related multifactorial syndrome with mainly genetic and environmental components.”

“First-degree relatives of PD patients are more likely to develop PD and other neuropsychiatric diseases. Environmental factors account for a high proportion of the pheno- typic variance of PD,” they wrote.

“Our findings provide information useful for counseling families of Parkinson’s patients,” they also said.

Additional studies are still needed to identify the environmental causes responsible for Parkinson’s susceptibility, and the genetic contribution for disease variability remains to be determined in other populations.

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‘PATH to PD’ Program Seeks to Deepen Understanding of Parkinson’s Onset, Progression

Michael J. Fox Foundation

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) will fund a new program to investigate the pathogenesis of Parkinson’s disease called “PATH to PD.”

The two-year program includes three research teams that will collaborate to investigate risks associated with genetics, environment and aging, while working with a common framework to gain a better understanding of the onset and progression of Parkinson’s.

Each PATH to PD-funded project will receive $2 million.

“The vast diversity of pathways implicated in Parkinson’s pathology to date indicates that multiple physiological routes can lead to PD, and these routes may intersect or be temporally dependent,” Todd Sherer, PhD, CEO of MJFF, said in a press release. “Through PATH to PD, our Foundation aims to encourage researchers to bring a holistic new approach to bear on refining today’s understanding of what Parkinson’s is — so that we can better strategize how to slow or stop the disease.”

Parkinson’s is not fully understood by scientists. Even though it is known the disease stems from gene-environment interactions as we age, the emerging picture of Parkinson’s is that of a vast, interwoven network culminating in a disease that varies greatly in cause, rate of progression, symptomology and treatment response.

All three teams will collaborate to build a common framework linking mechanisms through which genetics, environment and aging-associated risk and causal factors may lead to Parkinson’s disease.

University of Pittsburgh researchers, led by J. Timothy Greenamyre, MD, PhD, will seek out links between environmental and genetic triggers of the disease. Researchers will look into the mechanisms that lead neurotoxins to cause neurodegeneration and how these pathways are involved in interactions with genetic factors such as LRRK2 (leucine-rich repeat kinase 2), the leading genetic cause of the disease.

National Institutes of Health researchers, led by Andrew Singleton, PhD, will map the genetic effects in Parkinson’s by growing nerve cells from induced pluripotent stem cells, and map how various genetic alterations lead to the molecular and cellular changes associated with Parkinson’s.

Northwestern University researchers, led by D. James Surmeier, PhD, will investigate the link between aging and Parkinson’s. Using advanced gene-editing techniques, they will look at how cellular aging and related DNA and mitochondrial damage contribute to neurodegeneration in rodent and human cells.

These efforts have the common goal of developing a disease-modifying treatment for Parkinson’s disease, so that it can stop or slow disease progression.

For disease-modifying treatments to work best, however, they should target key underlying disease-causing pathways, which need to be identified and isolated first.

Some cases of Parkinson’s occur due to genetic factors, known as familial Parkinson’s disease. However, familial Parkinson’s is only a small fraction of all diagnoses of the disease. Informed guesses lean toward  environmental factors, including heavy metal or pesticide exposure, since aging still accounts for the greatest risk factor underlying this disease.

The fact that there is no identifiable cause of immediate contamination, researchers suspect this might be due to a lifetime accumulation of otherwise minor compound exposures that eventually lead to the development of the disease or contribute to a “switch” in Parkinson’s risk genes. Perhaps the process occurs naturally as medicine allows us to live longer, or perhaps it’s a combination of both.

“With Parkinson’s prevalence expected to double by 2040 to nearly 13 million people worldwide, our Foundation believes it is our obligation to continue building on current research momentum to eradicate this disease once and for all,” Sherer added.

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4 Possible Causes of Parkinson’s Disease

While the exact cause of Parkinson’s disease is currently unknown, scientists have come up with four possible theories according to the Mayo Clinic.

1. Genetics
There are certain genes which, when they become mutated, cause Parkinson’s disease. However, these mutated genes are very rare, except in cases where Parkinson’s runs in the family. There are also some gene variations which seem to slightly increase the risk of developing Parkinson’s.

MORE: Seven ways to help you self-manage Parkinson’s disease

2. Environment
Researchers think that there are some environmental factors and toxins which may trigger Parkinson’s disease, although they feel the increased risk is small.

3. Presence of Lewy bodies
Changes happening within the brain may also be a trigger for Parkinson’s disease. Lewy bodies are proteins found in brain cells which are biomarkers of the disease and may hold the key to finding out the exact cause.

4. Alpha-synuclein in Lewy bodies
There are many different substances found in Lewy bodies, but scientists are focusing on alpha-synuclein proteins. Alpha-synuclein proteins don’t break down; they form clumps in the cells which are thought to contribute to the disease.

MORE: The role of dopamine in the development of Parkinson’s disease

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