Can Damage in the Upper Gut Lead to Parkinson’s Disease?
—Accumulating evidence is pointing to the upper gastrointestinal tract as a source of Parkinson’s disease, with Helicobacter pylori emerging as a particular focus of interest.
A previous association between gastroesophageal dysfunction and subsequent development of Parkinson’s disease (PD) has been strengthened by a retrospective cohort study conducted by a trio of Boston-based experts.1 Specifically, in a population of more than 9300 patients, the risk of PD over an average of nearly 15 years was more than fourfold higher for those who had a history of gastric mucosal damage (MD)—erosions, esophagitis, ulcers, or peptic injury—on endoscopy relative to those who did not.1
The hypothesis that MD in the gut leads to PD is not new. Several epidemiological and clinical studies have previously suggested there might be a link between gut-related factors and PD. In animal models, neurodegenerative changes have been noted after injury to the gut.2 In a 2021 article reviewing evidence of a gut-to-brain pathogenesis of PD, numerous animal and clinical studies were cited.3
In humans, the best support for a gut-brain interaction in PD is perhaps provided by the high prevalence of Helicobacter pylori infection, a well-known cause of MD in the stomach, in patients with PD relative to the general population.4
Based on these and other studies, the vagus nerve is one of the suspected pathways for transferring pathology into the central nervous system, thus increasing the risk of PD in a subset of patients.2
When the gut’s involved, PD risk rises
The 9350 patients evaluated in this study were drawn from the Research Patient Data Registry, a database maintained by a collaboration between Mass General and Brigham and Women’s (MGB) hospitals.1 All patients had undergone an upper endoscopy between January 2000 and December 2005 and had no prior history of PD. Those with MD on endoscopy (n=2337) were matched in a 1:3 ratio with those without MD (n=7013) based on age, sex, and date of initial endoscopy. The mean age at endoscopy was 52.3 years.
After a mean follow-up of 14.9 years, PD developed in 2.2% of those with MD on endoscopy versus 0.5% of those without MD. Translated into an incidence rate ratio (IRR), the prevalence of PD at the end of follow-up, but before adjusting for covariates such as sex, race, constipation, dysphagia, and H pylori infection, was more than 4 times greater in those with MD versus those without MD (IRR 4.15, 95% confidence interval [CI] 2.89 to 5.97; P<.001). After adjustment, the greater rate of PD in those with MD still remained significant (IRR 1.76, 95% CI 1.11 to 2.51; P=.01).
What effect do covariates have?
When evaluating risk factors for PD, individuals with and without MD on initial biopsy were placed in 2 nested subgroups. In participants with MD on initial biopsy, the presence of H pylori was associated with a nearly fourfold increase in the adjusted odds ratio (aOR) of developing PD (aOR 3.84, 95% CI 1.22 to 12.13; P=.02). Similarly, a diagnosis of gastroesophageal reflux disease (GERD) also substantially increased the odds of PD (aOR 3.92, 95% CI 1.04 to 14.76; P=.04).
In the second nested subgroup, composed of those without MD on initial biopsy, patients with PD had a higher baseline prevalence of GERD, but no other covariate was associated with an increased risk of PD. Smoking, chronic use of nonsteroidal anti-inflammatories, and use of proton pump inhibitors were not associated with any effect on PD risk in either those with or without MD on initial biopsy.
The take-away for clinicians: be vigilant!
Like any other study, this one had some limitations. Among them were the authors’ inability to capture cases of PD and MD that were recorded outside of the MGB system. In addition, despite efforts to limit or negate it, surveillance bias toward patients with MD may have crept in. Still, as the authors stated, “given our large cohort, we were able to identify an incidence of PD comparable with the general population, so it is likely that we closely approximated the true population burden.”1
What’s not in doubt, the authors contend, is that the study strongly implicates MD—whether by GERD, H pylori infection, or another exposure—as a risk factor for PD. The senior author of this analysis, Trisha S. Pasricha, MD, MPH, who is affiliated with Beth Israel Deaconess Medical Center and is an instructor of medicine at Harvard Medical School, suggested these data should encourage further analysis of the association.
While the data support improved monitoring of patients with MD due to their increased clinical PD susceptibility, Dr. Pasricha cited a need for further research to confirm and more precisely understand how MD contributes to risk of a neurodegenerative disorder.
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