A recent genetic study linked Parkinson’s disease to inflammatory bowel disorders (IBDs), finding the two shared some risk variants. Now, the authors followed on with a large epidemiological study that cements the association. In the April 23 JAMA Neurology, researchers led by Inga Peter at Icahn School of Medicine at Mount Sinai, New York, reported that people with IBD were at elevated risk of developing Parkinson’s disease. Intriguingly, however, those who took anti-inflammatories directed against tumor necrosis factor (TNF) ran a lower risk than did even the general population. “Our results suggest that lowering systemic inflammation could reduce the risk of PD,” Peter told Alzforum. She is now examining other cohorts to determine if anti-inflammatories associate with lower PD incidence in the broader population, as well.
- People with IBD are more likely to get Parkinson’s.
- Those taking anti-TNF therapy, however, had a lower risk than did normal controls.
- The findings suggest that lowering systemic inflammation could help prevent PD.
Others agreed the data add to the picture of Parkinson’s as an inflammatory disease. “If you put all the data together, including human, animal, and microbiome, it strongly suggests that people who have a higher propensity for inflammatory responses have a higher propensity for PD,” Mark Cookson at the National Institutes of Health in Bethesda, Maryland, told Alzforum.
Researchers are increasingly finding links between Parkinson’s and inflammation in the gut. The enteric microbiome changes early in PD, and gut infections trigger α-synuclein release (Dec 2016 news; Apr 2017 news; Jul 2017 news).
Peter’s previous genetic study identified specific variants in the immune gene LRRK2 that raised or lowered risk for both PD and IBD (Jan 2018 news). The findings suggested that the diseases should tend to occur together, but epidemiological data were scarce, with only one previous study of 23 million people in Taiwan reporting an increased incidence of PD in people with IBD (Lin et al., 2016).
To confirm the association, Peter and colleagues analyzed data from 2000–2016 from two large medical databases, the Truven Health MarketScan Commercial Database and the Medicare Supplemental Database. Both host insurance claims from across the U.S. and contain millions of records. The authors selected 144,018 adults with IBD and matched them by age and sex to 720,090 unaffected controls. About 60 percent of the IBD patients had ulcerative colitis; the others had Crohn’s disease. The authors excluded people who had PD before their IBD diagnosis.
Among the whole group of cases and controls, 1,796 people had PD. People with IBD were 28 percent more likely to have Parkinson’s. This increased risk was seen mostly in men. Though the effect size was small, it was highly statistically significant. Peter noted that because both diseases are relatively rare, this association can only be detected in large cohorts. She is currently repeating the analysis in a Swedish cohort, and again finding an association.
The authors next looked at how anti-inflammatory treatment affected risk. Nine percent of the IBD patients, or 13,089 people, were taking an anti-TNF immunotherapy such as adalimumab, certolizumab, golimumab, or infliximab. They had a 78 percent lower risk of PD than other IBD patients did. In absolute terms, they had an incidence of 0.08 PD cases per 1,000 person-years, compared with 0.76 in the other IBD patients. Surprisingly, this incidence was also much lower than the 0.57 cases per 1,000 person-years seen in the control population.
Quyen Hoang at Indiana University School of Medicine, Indianapolis, called the lowered risk remarkable. “The link between TNF-associated inflammation and PD pathogenesis deserves further investigation to determine whether or not it is a causal relationship, and to uncover its potential mechanism,” he wrote to Alzforum.
Cookson was intrigued by the underlying biology implied by the TNF finding. TNF is a pro-inflammatory protein and often detrimental, so inhibiting it makes sense, he said. He suggested that future studies examine whether other anti-inflammatory drugs associate with lowered risk as well. “To be able to show that something that modifies the immune system also modifies PD risk is quite exciting,” Cookson said.
Peter plans to analyze large cohorts of people with rheumatoid arthritis and cirrhosis, who also take TNF inhibitors, to see if they have lower rates of PD, too. Because of the close association between the gut and PD risk, it is possible the therapy would only protect people with IBD, she noted. TNF inhibitors do not cross the blood-brain barrier, so Peter believes they would be most effective as preventatives to lower systemic inflammation and disease risk.
In an accompanying editorial, Clemens Scherzer at Brigham and Women’s Hospital, Boston, praised the strategy of using large data sets to analyze how existing drugs affect disease risk, calling it a “virtual repurposing” trial. “To conduct a prevention trial for PD from scratch would be incredibly difficult and expensive,” he wrote. “Virtual repurposing trials are incredibly powerful for generating novel hypotheses based on patients instead of animal models.”—Madolyn Bowman Rogers
- Do Microbes in the Gut Trigger Parkinson’s Disease?
- Rumblings of Parkinson’s: Gut Microbiome Shifts in Early Stage of Disease
- Put ’Em Up: Does α-Synuclein Help Fight Microbes in the Gut?
- Genetic Findings Link Parkinson’s to Crohn’s Disease, Inflammation
- Lin JC, Lin CS, Hsu CW, Lin CL, Kao CH. Association Between Parkinson's Disease and Inflammatory Bowel Disease: a Nationwide Taiwanese Retrospective Cohort Study. Inflamm Bowel Dis. 2016 May;22(5):1049-55. PubMed.
- Peter I, Dubinsky M, Bressman S, Park A, Lu C, Chen N, Wang A. Anti-Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease. JAMA Neurol. 2018 Apr 23; PubMed.