Milestones in elucidating the aetiopathogenesis of Parkinson’s disease have been few and far between. We step back to consider the whole entity. Constipation featured in the original description. Frequency of defecation deviates from that of controls three decades before median age of diagnosis, and infrequent bowel movements are associated with subsequent diagnosis. Abnormal bowel function becomes more apparent post-diagnosis. In contrast peptic ulceration has prodromal excess and little-in-the-way of local aftermath. Morphological and neurochemical changes associated with Parkinson’s disease are found in the enteric nervous system of oesophagus, stomach, duodenum and small- and large-intestine, in coeliac and para-verebral sympathetic ganglia and dorsal vagal nuclei[6–11]. Mitochondrial dysmorphology is seen in duodenal enterocytes in idiopathic parkinsonism. This, if replicated in enteric neurones and/or myocytes, and associated with dysfunction, may provide a mechanism behind slow gastrointestinal transit.
What initiates and perpetuates slow transit? A viral primer cannot be excluded: enteroviruses infect via the gastrointestinal tract and can have neurological sequelae; jejunal denervation is seen with human immunodeficiency virus infection, which can cause parkinsonism. In mice, intranasal inoculation with H5N1 influenza virus resulted in passage from enteric and dorsal root ganglia to brain stem. Ascent from here left a trail of microglial activation and dopaminergic degeneration. Could Helicobacter pylori, the organism causally associated with peptic ulcer, affect transit? The H. pylori serum immunoblot antibody profile predicts abnormal bowel function in probands with idiopathic parkinsonism and their spouses. In the presence of an anti-urease-B band, there was a four-fold increase in the odds of having abnormal function, irrespective of subject-group and urea-breath-test evidence of current infection. With an outer-membrane protein antibody band, there was a six-fold decrement.
Probands with idiopathic parkinsonism, aged ≤72.5 years, are twice, and siblings of probands three-times, as likely as controls to be seropositive for H. pylori anti-urease antibody. As in peptic ulcer/gastric carcinoma, there is no birth-cohort effect in antibody titre in probands in contrast to controls. This is compatible with causality and/or progressive immunocompromise. In no disease where H. pylori is causal is it present in every case. In Western populations, follow-up of cohorts tends to demonstrate a loss of H. pylori. This is generally attributed to widespread use of antimicrobials and acid-suppressants: low eradication rates cumulate with repeated exposure. The mainstay of anti-parkinsonian therapy, dopaminergic precursors, agonists and promoters, act locally and centrally to protect against experimental ulcers[19–21]. Whether therapeutic doses of dopaminergic agents suppress Helicobacter has not been explored, but agonists have been used to prevent duodenal ulcer relapse. Danish population registers show increased prescription of Helicobacter eradication drugs in the 5 years prior to diagnosis of Parkinson’s disease, compatible with prodromal peptic ulcer. Persistent infection might explain aggressive parkinsonism. Subjective motor assessment is, indeed, worse, relative to time since diagnosis, in Japanese probands with H pylori. Parkinson’s disease has been linked to rural living and farm experience. A mortality study of 26 US states found increased proportional mortality from Parkinson’s disease among livestock, but not arable, farmers. Zoonotic-transmission of other gastric Helicobacters may contribute to the aetiopathogenesis.
H. pylori is an arbiter for progression of brady/hypokinesia in idiopathic parkinsonism[5, 27]. Improvement in gait, in the year following successful blinded-active anti-H. pylori treatment, was replicated by open-active following initial placebo-randomisation. Gait plateaued over the subsequent two years. Improvement was independent of whether patients were untreated or receiving stable anti-parkinsonian therapy (levodopa use excluded to avoid iatrogenic fluctuations in performance). The effect is not related to infection-load: eradicating H. pylori detected only by molecular microbiology on culture-negative biopsies (‘low-density’ colonisation) occasioned similar improvement. Marked deterioration accompanied the natural experiment of eradication failure, even where persistence was at low-density. All failures were anti-nuclear antibody (ANA) seropositive. Moreover, ANA-positivity marked a poorer response to ‘successful’ eradication, perhaps indicating persistent undetected infection. Furthermore, irrespective of anti-urease ELISA seropositivity, the H. pylori serum immunoblot antibody profile against pathogenicity markers (cytotoxicity-associated gene-A product, vacuolating toxin-A and urease-B) is predictive of risk, severity and deterioration of idiopathic parkinsonism. The underlying mechanism may be self-limiting auto-immunity. Autoimmunity is supported by the finding of HLA-DR risk loci[29, 30]. It may have a peripheral (eg. skeletal muscle and cardiac mitochondria) as well as basal ganglia targets[12, 14].
Improvement in brady/hypokinesia following H. pylori eradication was mirrored by an increase in objectively-measured flexor-rigidity: rigidity increased in year one post-eradication, plateaued over the subsequent two. In a case study, this increase in rigidity coincided with onset of hydrogen-breath-test positivity for small intestinal bacterial overgrowth (SIBO), rigidity decreasing on regaining negativity. Overgrowth may drive a subsidiary rigidity-associated pathogenic pathway, and be a relatively non-specific and dose-related player in perpetuating neuronal damage[14, 27]. A 54% prevalence of glucose-hydrogen-breath-test positivity for SIBO is reported in Parkinson’s disease, versus 8% in controls. Peripheral inflammation can evade or compromise the blood–brain barrier. Overgrowth could provide a source of inflammation over a wide surface area with a strong haematogenous signal to microglia, as well as an afferent vagal. (Gut-brain communication still occurs after vagotomy.)
Overgrowth is not an innocent bystander in the gastrointestinal tract: there is bloating and flatulence, and clouds of lysosomes are seen in duodenal enterocytes in relation to luminal bacteria (unpublished observation: A. Curry, SMD, RJD, IB). Long thin, often complex-branching, mitochondria are seen in duodenal enterocytes, rather than the protein arrays encapsulated by a double-membrane associated with H. pylori. Overgrowth could drive homocysteine production and increase utilisation of vitamin B12 (a co-factor in homocysteine detoxification). Neither hyperhomocysteinaemia (43%) nor serum B12 concentration, in idiopathic parkinsonism, is explained by Helicobacter status. Since slow transit predisposes to reflux of colonic flora into the small-intestine, SIBO is likely to begin as a secondary phenomenon, but it may exacerbate gastrointestinal neuronal damage.
Here, we use surveillance data to explore the relationship of different facets of idiopathic parkinsonism to peripheral immuno-inflammatory activation, in the light of presence/absence of Helicobacter infection or of SIBO. Do any relationships between facets and blood leukocyte subset counts stand in patients free from anti-parkinsonian drugs, and are they robust enough to defy fluctuations in performance consequent on levodopa therapy? This builds on our demonstration of biological gradients of objective measures of facets on two systemic markers of inflammation, serum cortisol and tumour-necrosis-factor-α[34, 35]. Reale et al. have subsequently shown gradients of global scores of function and motor impairment on peripheral blood mononuclear cell production of cyto/chemokines and expression of nuclear factor κB. The setting is that, compared with controls, there is a relative lymphopenia in idiopathic parkinsonism, with an upward shift in the proportional distribution of natural-killer cells, a downward in B-cells. T-helper and cytotoxic T-cell distributions are platykurtic (greater proportions than expected above and below reference ranges). Neutrophil counts tended to be higher. These findings were not attributable to anti-parkinsonian treatment. That of a relative lymphopenia confirmed previous smaller studies[37–40].
We also explore the relationship between Helicobacter and hydrogen-breath-test status in idiopathic parkinsonism. Gastric pathophysiology, conducive to peptic ulceration in the prodrome, might protect against colonisation of the small-intestine from above: gastrin secretion, evoked by antral-predominant gastritis, enhances the acid-barrier. Later, the barrier might be compromised by cytokine-mediated inhibition (local or central) of acid secretion or by corporal gastric atrophy. After presentation, any Helicobacter gastritis is characteristically mild, atrophy absent, but inflammation associated with SIBO, secondary to caeco-ileal reflux, could progressively inhibit acid, with suppression of Helicobacter (as seen with proton pump inhibitors).