Upper GI Mucosal Damage Linked to Increased Risk of Parkinson Disease

A history of upper gastrointestinal mucosal damage may be associated with a greater risk of developing Parkinson disease (PD), according to findings from a recent study.¹

The study was published in JAMA Network Open and leveraged data for nearly 20,000 patients who underwent upper endoscopy with biopsy from a Mass General Brigham-based electronic database. Results showed those with positive endoscopic findings for mucosal damage had a greater risk of being diagnosed with PD compared to those without mucosal damage.¹

According to the World Health Organization, the prevalence of PD has doubled in the past 25 years, and global estimates showed more than 8.5 million individuals were living with PD in 2019. A neurodegenerative disorder predominately affecting dopaminergic neurons in the brain, PD causes problems with movement, mental health, sleep, pain, and other health issues. Although emerging research suggests PD results from a combination of genetic and environmental factors, and although a gut-first hypothesis has gained traction, the exact cause of PD is not known.^2,3

“A significant gap remains in understanding the relationship between broader upper GI mucosal damage, such as peptic ulcer disease and erosions, and the development of Parkinson disease, as most studies to date have focused on correlational links to a history of H pylori infection,” Trisha Pasricha, MD, MPH, a gastroenterologist at Massachusetts General Hospital and an instructor of medicine at Harvard Medical School, and colleagues wrote.¹

To determine the association between gastrointestinal mucosal damage and subsequent risk of being diagnosed with PD, investigators conducted a retrospective cohort study of patients undergoing upper endoscopy with biopsy between January 2000 and December 2005, with final follow-up assessments completed by July 31, 2023. The study was conducted within the Mass General Brigham system, and patients were selected using the Research Patient Data Registry, a Mass General Brigham-based electronic database storing data on patient demographics, encounters, medications, procedures, and billing codes.¹

Using the search query tool, investigators identified a cohort of 18,305 patients who had a history of upper endoscopy with biopsy between 2000 and 2005 and no history of PD prior to initial upper endoscopy, 11,293 of whom were included in the study. Patients with positive endoscopic findings for mucosal damage, including erosions, esophagitis, ulcers, and peptic injury, were matched in a 1:3 ratio to patients without mucosal damage based on age, sex, and date of upper endoscopy.¹

Each participant was followed up until a diagnosis of Parkison disease; death; or, in the absence of a PD diagnosis, censoring at an outpatient appointment with no subsequent follow-up for > 2 years, representing loss to follow-up, or until July 31, 2023. Investigators identified cases of PD through ICD-9 codes confirmed by a history of PD-specific prescriptions.¹

Investigators additionally conducted 2 nested case-control analyses, including one within the group of patients previously found without mucosal damage and the second within the group of patients previously found to have mucosal damage. In both nested analyses, cases were matched to controls without PD in a 1:2 ratio based on age at upper endoscopy, sex, and date of each case’s PD diagnosis by incidence density sampling.¹

Of the 11,293 patients included in the study, 9350 were included in the Cox proportional hazards model. Among this cohort, the mean age was 52.3 (Standard deviation [SD], 20.3) years and the majority of patients (55.4%) were male and White (73.7%). Additionally, investigators noted most participants underwent endoscopy between the ages of 50 and 64 years (30.4%). Of these patients, 2337 were found to have evidence of mucosal damage on endoscopy while 7013 did not.¹

Among all patients included in the study, 2338 patients had mucosal damage, and 52 (2.2%) were later diagnosed with PD. Of the 8955 patients without mucosal damage, 48 (0.5%) were later diagnosed with PD, indicating a notably increased likelihood of PD diagnosis among patients with mucosal damage compared with those without (2.2% vs 0.5%; P <.001; IRR, 4.15; 95% CI, 2.89-5.97; P <.001).¹

After adjusting for additional covariates including age at endoscopy, sex, race, Charlson-Deyo Comorbidity Index, constipation, dysphagia, and H pylori, the risk associated with mucosal damage remained pronounced (hazard ratio [HR], 1.76; 95% CI, 1.11-2.51; P = .01). Further analysis revealed age (HR, 1.04; 95% CI, 1.02-1.05; P <.001), CCI (HR, 1.21; 95% CI, 1.09-1.35; P <.001), constipation (HR, 2.65; 95% CI, 1.72–4.08; P <.001), and dysphagia (HR, 2.33; 95% CI, 1.52-3.56; P <.001) as factors associated with an increased risk of developing PD.¹

Within the first nested subgroup of patients with mucosal damage, investigators did not note any significant demographic differences between patients with a clinical diagnosis PD and those without, although they pointed out patients with PD had a higher baseline prevalence of chronic NSAID use and GERD. Upon analysis, H pylori (adjusted odds ratio [aOR], 3.84; 95% CI, 1.22-12.13; P = .02) and GERD (aOR, 3.92; 95% CI, 1.04-14.76; P = .04) were associated with a markedly higher probability of developing PD.¹

Within the second nested subgroup of patients without mucosal damage, investigators again noted no significant demographic differences between patients with a clinical diagnosis of PD and those without, although patients with PD had a higher baseline prevalence of GERD. Chronic NSAID use, chronic smoking, GERD, PPI use, and H pylori were incorporated into this analysis, but investigators noted none of these covariates were associated with an increased risk of developing PD.¹

Investigators acknowledged multiple limitations to these findings, including the inability to capture cases of PD diagnosed and treated outside the MGB system; differences in baseline age distribution and mean CCI between patients with MD compared with those without; reliance on ICD codes for multiple exposures and outcomes; small sample sizes in the nested case-control analyses; and the risk of bias from unknown confounding.¹

“These findings highlight the necessity for heightened monitoring of patients with MD given their increased clinical PD susceptibility and the importance of establishing gut biomarkers,” investigators concluded.1 “With PUD globally affecting upwards of 8.09 million people and H pylori infection even more widespread, timely detection and treatment of H pylori infection, along with MD management, may prove crucial to early recognition of risk of and potentially intervention against PD.”

References

1. ^{Chang JJ, Kulkarni S, Pasricha TS. Upper Gastrointestinal Mucosal Damage and Subsequent Risk of Parkinson Disease. JAMA Netw Open. doi:10.1001/jamanetworkopen.2024.31949}
2. ^{World Health Organization. Parkinson Disease. Newsroom. August 9, 2023. Accessed September 6, 2024. https://www.who.int/news-room/fact-sheets/detail/parkinson-disease}
3. ^{Parkinson’s Foundation. Understanding Parkinson’s. Accessed September 6, 2024. https://www.parkinson.org/understanding-parkinsons/what-is-parkinsons}