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Appendix Removal Tied to Lower Risk of Parkinson’s Disease

alpha-synuclein in GI tract
Aggregates of alpha-synuclein in the neurons of the appendix. | Van Andel Research Institute

A research team has found that surgical removal of the appendix is associated with a decreased risk of developing Parkinson's disease. The new study , based on an analysis of health records for over 1.6 million people in Sweden, was published in the October 31 issue of Science Translational Medicine.

The findings build on previous research suggesting that the appendix and other parts of the gastrointestinal (GI) tract play a pivotal role in the development of Parkinson's disease, a neurodegenerative disorder with no cure. However, the researchers stress that further studies are necessary to confirm the effect of appendectomy on the risk of Parkinson's.

As one of the most common neurological disorders, Parkinson's represents a massive health and economic burden in the U.S. and worldwide. According to the Parkinson's Foundation, the condition affects more than 10 million people globally, and is responsible for an estimated $25 billion per year in medical costs and lost income in the U.S. alone. The foundation's recent study projected that 1.2 million Americans will be living with the condition by 2030, further increasing the burden on patients and health providers.

Some scientists have therefore focused on understanding the early stages of the disease in the hopes of devising preventative therapies. For example, previous research has demonstrated that abnormalities in the GI tract are common in patients with Parkinson's. These symptoms can precede motor deficits by as many as 20 years, according to Viviane Labrie, assistant professor at the Van Andel Research Institute in Grand Rapids, Michigan and senior author of the new study.

Furthermore, the GI tract has been shown to contain high quantities of α-synuclein — a component of the protein clumps that form in the brains of Parkinson's patients. Labrie noted that α-synuclein can travel up the nerve that connects the GI tract to the brain, where it could potentially seed itself and have neurotoxic effects.

"This intriguing connection between the GI tract and the early processes in Parkinson's had us interested in trying to understand how the gut could be involved in Parkinson's disease," she said.

To solve this mystery, Bryan Killinger, a postdoctoral fellow at the Van Andel Research Institute and colleagues conducted a study to investigate whether the appendix — a small organ that is commonly removed with surgery when inflamed — could be important to the GI origins of Parkinson's.

The research team began by analyzing the Swedish Patient Registry, a database that has documented surgical procedures and medical history in the Swedish population for over 50 years. The authors looked at data from over 1.6 million Swedes and determined that approximately 550,000 individuals had an appendectomy. They matched each of these patients with two individuals who did not have an appendectomy, and also identified 2,200 other patients who were diagnosed with Parkinson's.

The scientists found that Parkinson's was diagnosed in 1.16 out of every 1000 people in the appendectomy group, compared to 1.4 out of every 1000 people in the general population. Overall, appendectomy was associated with a 19.3% decrease in the risk of developing Parkinson's, according to the authors.

Interestingly, the protective effect associated with appendectomy was most pronounced among rural residents. Individuals with an appendectomy living in rural areas displayed a 25.4% decrease in risk of Parkinson's, but there was no protective benefit associated with the procedure for those living in urban areas.

"Those findings told us that there is something that we don't quite understand yet, but something that's associated with environmental risk factors," said Lena Brundin, an associate professor at the Center for Neurodegenerative Science and a co-author of the study.

The team then turned to a second dataset named the Parkinson's Progression Markers Initiative, which contains detailed information about Parkinson's diagnosis and the age of disease onset gathered from clinical sites in the U.S., Europe, Israel and Australia. By examining the medical history of 849 Parkinson's cases, the authors concluded that the onset of the disease was delayed by 3.6 years on average in individuals who had an appendectomy at least 30 years before the condition appeared.

To shed further light on the molecular links between the appendix and Parkinson's, Killinger's team also used microscopy to examine 48 samples of appendix tissue from healthy individuals. Remarkably, they found 46 of the samples contained chemically active α-synuclein that was prone to aggregation — a harmful "clumping" behavior. The aggregates were equally abundant in both young and old people, as well as in both normal and inflamed appendix tissue.

"We don't know fully what the normal function of α-synuclein is in the brain either," said Patrik Brundin, director of the Center for Neurodegenerative Science at the Van Andel Research Institute and a co-author of the study. "But the type of aggregates we saw in the appendix are very similar to the pathological form of synuclein seen inside the brains of people with Parkinson's disease."

The authors stress that their study does not mean appendectomy should be used as a preventative measure against Parkinson's, nor does it mean that individuals who retain their appendixes are destined to develop the disorder. Labrie said that appendectomies performed to prevent Parkinson's could have unintended consequences on the microbiome and other GI-related issues.

However, therapies that target α-synuclein accumulation in the appendix and gut could represent a potential therapeutic strategy to reduce the risk of Parkinson's later in life. Researchers should also investigate whether there are other places in the GI tract that could serve as hubs for α-synuclein aggregates, Labrie said.

The team plans to conduct further studies to elucidate how the appendixes of those with Parkinson's differ from healthy individuals on the genetic and cellular level. "We really want to get down to these mechanisms so that we can find new targets for early diagnostics and for therapies," she said.

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Joseph Cariz