These Gastrointestinal Syndromes May Predict Parkinson Disease Risk

Preceding onset of specific gastrointestinal (GI) syndromes may predict the development of Parkinson disease (PD), giving credence to Braak’s hypothesis, according to study findings published in the journal Gut.

Many studies have demonstrated that α-synuclein concentrations in the enteric nervous system are higher in individuals with PD compared with healthy individuals, resulting in the formulation of Braak’s hypothesis. Braak’s hypothesis states that “α-synuclein pathology progresses from peripheral sites such as the [enteric nervous system] to the [central nervous system] via vagal or olfactory pathways … introducing the concept that the gastrointestinal (GI) tract might serve as a gateway for environmental factors that induce α-synuclein misfolding … [leading] to PD.”

Researchers in the United States conducted a nationwide, case-control, cohort study, obtaining data on 24,624 patients diagnosed with PD between January 1, 2005 and July 1, 2021 from the TriNetX Analytics Research Network database. Only individuals with at least 2 prescriptions of an antiparkinsonian medication and a documented ambulatory visit at least 2 years prior to PD diagnosis were included in the cohort.

Next, the researchers matched this cohort with a control cohort of patients without PD based on age, sex, race, and ethnicity in pairwise fashion. They sought to determine the incidence of GI syndromes and interventions before PD diagnosis compared with 8,267,744 individuals without PD, Alzheimer disease (AD), or cardiovascular disease (CVD) as well as compared with 36,187 individuals who developed AD and 528,207 individuals who developed CVD.

Eighteen GI syndromes were of interest, including:

• Achalasia
• Dysphagia
• Gastroesophageal reflux disease (GERD)
• Gastroparesis (GP)
• Functional dyspepsia (FD)
• Paralytic ileus (PI)
• Diarrhea
• Constipation
• Irritable bowel syndrome (IBS) with constipation (IBS-C)
• IBS with diarrhea (IBS-D)
• IBS without diarrhea
• Intestinal pseudo-obstruction
• Fecal incontinence (FI)
• Crohn’s disease (CD)
• Ulcerative colitis (UC)
• Microscopic colitis (MC)
• Appendectomy
• Vagotomy

After comparing the cohort with PD to the other 3 cohorts (normal, AD, and CVD), the researchers discovered that all 18 GI syndromes and interventions significantly increased in the PD cohort compared with the healthy cohort (odds ratio [OR], >1; P <.05 for all).

Of these conditions, only dysphagia, GP, IBS-C, IBS without diarrhea, and constipation were specifically associated with PD (OR, >1; P <.05 for each) after comparison with the healthy individuals, the AD cohort, and the CVD cohort.

Vagotomy, CD, and UC were not associated with PD. IBS with constipation demonstrated PD-specificity in the case-control analysis compared with the control cohort (OR, 4.11), while intestinal pseudo-obstruction demonstrated PD-specificity in terms of risk for developing PD compared with the control cohort (relative risk [RR], 1.84).

Compared with individuals who did not develop any conditions, including PD, those who developed PD were more likely to present in the 2 years preceding PD diagnosis with GP (OR, 4.64; P <.0001), dysphagia (OR, 3.58; P <.0001), IBS without diarrhea (OR, 3.53; P <.0001), and constipation (OR, 3.32; P <.0001).

Correspondingly, the risk of developing PD was higher in individuals with GP (RR, 2.43; P <.05) dysphagia (RR, 2.27; P <.05), IBS without diarrhea (RR, 1.17; P <.05), and constipation (RR, 2.38; P <.05).

In contrast, having an appendectomy decreased the risk of developing PD (RR, 0.48), resulting in speculation the role the appendix may play in PD pathogenesis.

“This study is the first to establish substantial observational evidence that the clinical diagnosis of not only constipation, but also dysphagia, GP and IBS without diarrhea might specifically predict the development of PD …,” the researchers concluded. “These findings warrant alertness for GI syndromes in patients at higher risk for PD …”

Study limitations include those intrinsically associated with use of electronic health record data and documentation, such as incomplete data, coding errors, and lack of validation with objective findings to confirm diagnoses.