Gastrointestinal syndromes preceding a diagnosis of Parkinson’s disease: testing Braak’s hypothesis using a nationwide database for comparison with Alzheimer’s disease and cerebrovascular diseases

Abstract

ObjectiveBraak’s hypothesis states that Parkinson’s disease (PD) originates in the gastrointestinal (GI) tract, and similar associations have been established for Alzheimer’s disease (AD) and cerebrovascular diseases (CVD). We aimed to determine the incidence of GI syndromes and interventions preceding PD compared with negative controls (NCs), AD and CVD.DesignWe performed a combined case-control and cohort study using TriNetX, a US based nationwide medical record network. Firstly, we compared subjects with new onset idiopathic PD with matched NCs and patients with contemporary diagnoses of AD and CVD, to investigate preceding GI syndromes, appendectomy and vagotomy. Secondly, we compared cohorts with these exposures to matched NCs for the development of PD, AD and CVD within 5 years.ResultsWe identified 24 624 PD patients in the case-control analysis and matched 18 cohorts with each exposure to their NCs. Gastroparesis, dysphagia, irritable bowel syndrome (IBS) without diarrhoea and constipation showed specific associations with PD (vs NCs, AD and CVD) in both the case-control (odds ratios (ORs) vs NCs 4.64, 3.58, 3.53 and 3.32, respectively, all p<0.0001) and cohort analyses (relative risks (RRs) vs NCs 2.43, 2.27, 1.17 and 2.38, respectively, all p<0.05). While functional dyspepsia, IBS with diarrhoea, diarrhoea and faecal incontinence were not PD specific, IBS with constipation and intestinal pseudo-obstruction showed PD specificity in the case-control (OR 4.11) and cohort analysis (RR 1.84), respectively. Appendectomy decreased the risk of PD in the cohort analysis (RR 0.48). Neither inflammatory bowel disease nor vagotomy were associated with PD.ConclusionDysphagia, gastroparesis, IBS without diarrhoea and constipation might specifically predict Parkinson’s disease.

Gastrointestinal Mucosal Damage and Subsequent Risk of Parkinson’s Disease

“…Consistent with prior studies 6 , our investigation did not establish a connection between GERD and PD, though there is well-documented relationship between GERD and MD, and we observed that GERD and PPI use was significantly higher in our MD cohort (Table 1). There are limitations utilizing ICD codes for GERD diagnosis, and likely some insufficiency of what is often now a clinical diagnosis of GERD based on symptoms and empiric response to PPI therapy.…”

“…However, the precise inciting factor triggering PD pathology in the gut remains elusive, complicating efforts to fully understand PD’s onset. A recent nationwide study found no association between a history of inflammatory bowel disease and subsequent risk of PD, suggesting that MD in the distal GI tract where pelvic rather than vagal innervation is the hallmark, may play a less important role in pathogenesis 6 .…”

Hospital-treated infections and subsequent Parkinson’s disease risk: a register-based sibling comparison study

“…The disease seems to originate in the gut in a subset of patients, and there is evidence of gastrointestinal syndromes preceding the diagnosis of Parkinson’s disease. 3 …”

“…Therefore, we hypothesized that serious infections (treated in hospital) of the gastrointestinal tract, but not all other sites, would be associated with a raised risk of Parkinson’s disease. The prodromal stage of Parkinson’s disease is notably variable in duration at the level of the individual, but is on average 10 years in the entire patient group, when some early gastrointestinal symptoms such as constipation, 3 , 11 dysphagia, gastroparesis and irritable bowel syndrome without diarrhoea occur. 3 Therefore, in this study, we considered age at infection to address possible bias due to reverse causation, where prodromal Parkinson’s disease activity may increase infection risk.…”

Machine learning-based meta-analysis reveals gut microbiome alterations associated with Parkinson’s disease

“…However, PD manifests with a plethora of both motor and non-motor symptoms, many of which involve the gastrointestinal (GI) tract [6][7][8] . Among the latter, gastroparesis, gut inflammation, increased intestinal permeability, and constipation are frequently observed 8 and some of these GI symptoms have been shown to be predictive of PD 7 . Surprisingly, the GI tract involvement can precede motor symptoms by many years.…”