Early detection of these conditions might help identify patients at risk for PD, potentially prompting preventive strategies, the researchers suggest.
The results of previous experimental studies by the team supported the Braak hypothesis, which states that idiopathic PD originates in the gut in a subset of patients. However, no previous study had investigated a broad range of gastrointestinal (GI) symptoms and syndromes that might occur prior to a PD diagnosis.
Given their preclinical work, the authors were not surprised to find that certain GI syndromes were specifically associated with PD, even when compared with Alzheimer's disease (AD) and cerebrovascular disease (CVD), principal author Pankaj Jay Pasricha, MBBS, MD, of Mayo Clinic Arizona, Scottsdale, told Medscape Medical News. However, they were "impressed by the strength of the associations."
"Experts have known for a very long time that constipation is a potential risk factor for PD, so this study adds to the list of GI conditions that could potentially be risk factors," he said.
The study was published online August 24 in Gut.
To determine the incidence of GI syndromes and interventions preceding PD, the investigators performed a combined case-control and cohort study using a US-based nationwide medical record network.
First, they compared 24,624 individuals with new-onset idiopathic PD with the same number of matched negative controls (NCs), as well as 19,046 people with AD and 23,942 with CVD to investigate the presence of preexisting GI conditions, which the researchers referred to as "exposures." Overall, the mean age was about 70, and about half of those studied were women.
Eighteen conditions covering the entire GI tract were investigated. These included achalasia, dysphagia, gastroesophageal reflux disease, gastroparesis, functional dyspepsia, paralytic ileus, diarrhea, irritable bowel syndrome (IBS) with and without diarrhea, intestinal pseudo-obstruction, fecal incontinence, Crohn's disease, ulcerative colitis, and microscopic colitis, as well as appendectomy and vagotomy.
All GI syndromes were significantly increased in the PD group compared with NCs (odds ratio [OR] > 1). However, only preexisting dysphagia (OR, 3.58), gastroparesis (OR, 4.64), functional dyspepsia (OR, 3.39), intestinal pseudo-obstruction (OR, 3.01), diarrhea (OR, 2.85), constipation (OR, 3.32), IBS with constipation (OR, 4.11), IBS with diarrhea (OR, 4.31), IBS without diarrhea (OR, 3.53), and fecal incontinence (OR, 3.76) produced ORs that were numerically greater than the upper limit of the negative exposures.
In addition, only gastroparesis, dysphagia, IBS with constipation, IBS without diarrhea, and constipation were specific for PD, compared with the AD and CVD groups (OR > 1). After correction for false discovery rate, though, gastroparesis and constipation did not remain significantly different compared with the AD and CVD groups.
Other preexisting GI conditions not only were significantly associated with PD but also showed strong associations with the AD and CVD groups.
To validate the case-control analyses, the team set up a complementary cohort study. Eighteen cohorts — each diagnosed with one of the GI conditions in the case-control analysis — were compared with their respective NC cohorts for the prospective risk of developing PD, AD, or CVD within 5 years.
Gastroparesis, dysphagia, IBS without diarrhea, and constipation showed specific associations with PD vs NCs, AD, and CVD in the cohort analysis. Their relative risks (RRs) vs NCs were 2.43, 2.27, 1.17, and 2.38, respectively.
Functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not PD-specific, but IBS with constipation and intestinal pseudo-obstruction showed PD specificity in both the case-control (OR, 4.11) and cohort analyses (RR, 1.84).
Appendectomy decreased the risk for PD in the cohort analysis (RR, 0.48), but neither inflammatory bowel disease nor vagotomy was associated with PD.
"This study is the first to establish substantial observational evidence that the clinical diagnosis of not only constipation but also dysphagia, gastroparesis, and IBS without diarrhea might specifically predict the development of PD, whereas other exposures were less specific," the researchers write.
However, Pasricha said, "there is no need for alarm." Clinicians should reassure patients that "the overall risk for developing PD is low. The overwhelming majority of patients with these GI conditions will never develop PD."
His team will be doing experimental work on the biological mechanisms that might explain the current study's findings. "In addition, the US National Institutes of Health has issued a call for proposals to perform research in patients that could help understand these associations better," he said.
Body or Brain?
The Parkinson's Foundation's National Medical Advisor, Michael S. Okun, MD, called the study "fascinating."
The findings "confirm many other studies showing that GI symptoms can precede a Parkinson's disease diagnosis," he told Medscape Medical News.
Although the study was designed to test the Braak hypothesis, "the dataset really cannot confirm or refute Braak pathology, which can only be accomplished with comparison to postmortem samples," he added.
"The raging debate in the field of body-first vs brain-first Parkinson's may be somewhat artificial, especially if we consider that Parkinson's is not one disease," Okun noted. "It will take clinical data, pathology, and the collaboration of many researchers to solve the puzzle."
"The Foundation continues to monitor all the advancements in the 'gut' Parkinson field," he said. "We do not recommend at this time changing the approach to clinical care based on this data."
No funding or competing interests were declared. Okun has no relevant disclosures.
Gut. Published online August 24, 2023. Full text
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Cite this: These Four GI Conditions May Predict Parkinson's Disease - Medscape - Aug 31, 2023.