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Could the Appendix Be Involved in Triggering Parkinson's Disease?
New Findings on the Brain-Gut Connection

ARTICLE IN BRIEF

Figure

PROTEINASE-K-RESISTANT ALPHA-SYNUCLEIN (red) in the appendix of healthy individuals. Tissue distribution of proteinase K-resistant alpha-synuclein aggregates in a representative cross section of the human appendix (i and ii), in the muscularis externa (iii), and mucosa of the appendix (iv).

An analysis of medical records and pathologic findings from a population-based database found that those who had undergone appendectomy had a lower risk of Parkinson's disease (PD). The findings fit into a growing body of research that points to a brain-gut connection in PD.

A study using two large patient databases suggests that people who have had their appendix removed early in life are at lower risk for Parkinson's disease (PD), and that an appendectomy may also delay the onset of motor symptoms in those with PD.

The study, published online October 31 in ScienceTranslationalMedicine, also includes pathological findings suggesting that Lewy bodies, the hallmark clumps of protein found in the brains of PD patients, may originate from the appendix.

The study does not prove cause and effect between the appendix and the risk of Parkinson's, but the findings do fit into a growing body of research that points to a brain-gut connection in PD, the study authors and independent movement disorder experts agreed.

“We are thinking of Parkinson's not as a movement disorder but as a multisystem disorder that includes the gastrointestinal tract,” said Viviane Labrie, PhD, the study's senior author and an assistant professor at the Van Andel Research Institute Center for Neurogenerative Science in Grand Rapids, MI. “The appendix may be involved in the early triggering of the disease,” said Dr. Labrie.

Her team's analyses found that appendectomy early in life lowered the risk of Parkinson's by anywhere from approximately 19 to 25 percent. But Dr. Labrie and other Parkinson's experts interviewed by NeurologyToday cautioned that the findings, while certainly interesting, have no current implications for treatment or disease prevention.

“One thing we are not advocating for is preventive appendectomy, even for at-risk individuals,” Dr. Labrie said.

The study authors noted that gastrointestinal (GI) dysfunction — such as constipation, for example — is a common non-motor symptom of PD, often preceding the onset of motor symptoms by as many as 20 years. They also noted that previous studies have found that abnormally folded alpha-synuclein protein, which makes up the Lewy bodies that form in the brains of people with PD, has been detected in the GI tract of PD patients.

Dr. Labrie said her team decided to focus on the appendix because the GI tract is “a large territory, and we wondered where we should look to better understand the role of the GI tract in Parkinson's disease.”

She said that although the appendix is often thought of as a useless organ, it actually plays an important role in the immune system and helps in the storage and regulation of gut bacteria.

PATIENT DATABASES ANALYZED

The study had three components. The researchers first analyzed data from the National Swedish Patient Registry, which includes health records for nearly 1.7 million people followed up to 52 years. The registry contains medical diagnoses and surgical codes for the Swedish population starting in 1964. A total of 551,647 people who had had an appendectomy were identified in the registry and then compared to people who did not have their appendix removed.

PD incidence was 1.60 per 100,000 person-years among individuals who had an appendectomy versus 1.98 for controls, the study reported.

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AGGREGATED ALPHA-SYNUCLEIN (red) in the neurons of the appendix (green); nuclei of the appendix nerve cells are colored in blue.

“This signifies that the overall risk of developing PD was significantly reduced by 19.3 percent in appendectomized individuals compared to the general population,” the report said.

The analysis also found that the age of PD diagnosis was, on average, 1.6 years later in individuals who had had an appendectomy 20 or more years prior as compared with PD patients who did not have an appendectomy.

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DR. VIVIANE LABRIE: “We are thinking of Parkinsons not as a movement disorder, but as a multisystem disorder that includes the gastrointestinal tract. We think the appendix may be involved in early triggering of the disease.”

Previous epidemiological studies have found an association between rural living and a higher risk for Parkinson's, perhaps because of exposure to pesticides. With that in mind, the researchers for the current study compared rural residents to urban ones. They found that people with an appendectomy living in rural areas had a 25.4 percent decrease in PD risk, but there was no benefit of appendectomy on PD risk for those in urban areas. There was also a delay in symptoms for rural residents with PD who had an appendectomy.

“These findings suggest that appendectomy influences environmental risk factors for PD, specifically for individuals living in rural environments,” wrote the research team, which included scientists from Lund University in Sweden, Michigan State University, and Northwestern University.

In the second part of the study, researchers analyzed data from the Parkinson's Progression Markers Initiative (PPMI), which is a large comprehensive clinical PD data set. Using a cohort of 849 PD cases, the researchers found that the age of PD onset was delayed, on average, by 3.6 years in individuals who had an appendectomy at least 30 years before disease onset, compared to individuals without the surgery. Once PD developed, there was no difference in severity of symptoms between those who had an appendectomy and those who had not.

“This suggested that the appendix might primarily modify events before clinical onset of symptoms,” the researchers reported.

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DR. KATHLEEN SHANNON: “There are no therapeutic implications at this time, but the finding may help us put the pieces together to better understand the gut-brain link in the genesis of Parkinsons disease.”

The researchers also used the PPMI database to look at some subsets of patients. They found that appendectomy delayed the age of onset of PD in persons with a family history of PD, though not for people without a family history. But there was not a similar benefit from appendectomy for persons with a common genetic mutation associated with familial PD.

“This suggest that an appendectomy may be more protective against non-genetic, environmental causes of PD,” the researchers said.

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DR. CONNIE MARRAS said the “thoroughness of the epidemiologic aspects of this paper are quite impressive,” particularly because the researchers used “complementary datasets with different strengths and weakness and largely their findings are in agreement.”

PATHOLOGICAL FINDINGS

In the third part of the study, the researchers used immunochemistry to determine whether alpha-synuclein pathology was present in the appendix of people in the general population. They analyzed tissue from 48 people who had their appendix removed. Their tissue analysis found that abnormally folded alpha-synuclein protein was pervasive in the appendix of people who had and did not have PD. Disease-associated forms of alpha-synuclein were even found in healthy (non-PD) people younger than 20.

“This tells us that the appendix is a storage tank or hub for the clumps of protein associated with Parkinson's,” said Dr. Labrie.

Dr. Labrie said it is not fully understood what alpha-synuclein does, though it is thought to be involved in nerve communication and signaling to the immune system. She said that it is possible that in rare instances the clumped alpha-synuclein protein travels via the vagus nerve from the appendix to the brain, where it can have toxic effects on neurons.

She said the findings provide avenues for further research into the factors that may trigger the spread of alpha-synuclein and push a person toward getting PD.

EXPERT COMMENTARY

“I thought the study provided a very intriguing narrative regarding the role of the appendix in the risk of developing Parkinson's disease,” said Kelvin Chou, MD, professor of neurology and co-director of the Surgical Therapies Improving Movement Program at the University of Michigan, but he noted that it “is still a hypothesis and has not been proven definitively.”

He said the GI tract involvement in PD was known over a decade ago; the theory was that the abnormal protein spreads from the gut via the vagus nerve to the midbrain and on to the cortex. Dr. Chou said it would have been interesting if the researchers had used the databases to also see if other types of abdominal surgery influenced PD risk.

He said the findings related to the appendix raise the possibility that “maybe there is some therapeutic agent that could be used to prevent it (the abnormal protein) from spreading to the brain.” But Dr. Chou said that even if this study is corroborated, there are likely other mechanisms that could lead to the development of Parkinson's.”

“Right now a popular theory is that some people have this predilection for Parkinson's disease but do not develop it until something in the environment triggers a cascade of events that leads to neurodegeneration in the brain,” said Dr. Chou, who in the past 12 months received consulting fees from Sunovion Pharmaceuticals.

Connie Marras, MD, PhD, associate professor of neurology at University of Toronto and a movement disorders specialist at Toronto Western Hospital, said the “thoroughness of the epidemiologic aspects of this paper are quite impressive,” particularly because the researchers used “complementary datasets with different strengths and weakness and largely their findings are in agreement.”

Still, she noted that research using large datasets has limitations because of the way information is classified.

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DR. KELVIN CHOU: “I thought the study offered very intriguing narrative regarding the role of the appendix in the risk of developing Parkinsons disease, but it is still a hypothesis and has not been proven definitively.”

Dr. Marras conducted a study, published in 2016, using a large Canadian database and found no association between appendectomy and PD risk. The study covered a shorter period of time than the current analysis, which used the Swedish registry and has more than 50 years of information on some patients.

“Ours was restricted to a follow-up of less than 20 years for the people who were followed the longest,” which could have made for a different outcome, said Dr. Marras. “Parkinson's disease is a condition that begins pathologically long before it expresses clinically or is diagnosed.”

She is now studying whether patterns of prescription drug use influence the incidence and progression of PD.

Kathleen Shannon, MD, FAAN, Detling professor and chair of neurology at University of Wisconsin School of Medicine and Public Health, said epidemiologic studies also show that inflammatory bowel disease (IBD) increases the risk of developing Parkinson's disease (and treatment of IBD with TNF-alpha inhibitors reduces that increased risk), and that truncal vagotomy reduces the risk of Parkinson's disease.

As for this latest study focused on the appendix, “There are no therapeutic implications at this time,” Dr. Shannon said in an email to Neurology Today, “but the finding may help us put the pieces together to better understand the gut-brain link in the genesis of Parkinson's disease.”

LINK UP FOR MORE INFORMATION:

• Killinger BA, Madaj Z, Sikora JW, et al. The vermiform appendix impacts the risk of developing Parkinson's disease http://stm.sciencemag.org/content/10/465/eaar5280. Sci Transl Med 2018; 10(465). pii: eaar5280.