Blood profile holds clues to role of infection in a premonitory state for idiopathic parkinsonism and of gastrointestinal infection in established disease

Abstract

The two-stage neuroinflammatory process, containment and progression, proposed to underlie neurodegeneration may predicate on systemic inflammation arising from the gastrointestinal tract. Helicobacter infection has been described as one switch in the pathogenic-circuitry of idiopathic parkinsonism (IP): eradication modifies disease progression and marked deterioration accompanies eradication-failure. Moreover, serum Helicobacter-antibody-profile predicts presence, severity and progression of IP. Slow gastrointestinal-transit precedes IP-diagnosis and becomes increasingly-apparent after, predisposing to small-intestinal bacterial-overgrowth (SIBO). Although IP is well-described as a systemic illness with a long prodrome, there has been no comprehensive overview of the blood profile. Here, it is examined in relation to Helicobacter status and lactulose-hydrogen-breath-testing for SIBO.A robust finding of reduced lymphocyte count in 126 IP-probands and 79 spouses (without clinically-definite IP), compared with that in 381 controls (p < 0.001 in each case), was not explained by Helicobacter-status or breath-hydrogen. This complements a previous report that spouses were 'down-the-pathway' to 'clinically-definite' disease. In 205 other controls without clinically-definite IP, there were strong associations between sporadic cardinal features and immunoglobulin class concentration, not explained by Helicobacter-status. Premonitory states for idiopathic parkinsonism associated with relative lymphopenia, higher serum immunoglobulin concentrations and evidence of enteric-nervous-system damage may prove viral in origin.Although only 8% of the above 79 spouses were urea-breath-test-positive for Helicobacter, all 8 spouses with clinically-definite IP were (p < 0.0001). Transmission of a 'primer' to a Helicobacter-colonised recipient might result in progression to the diagnostic threshold.Twenty-five percent of the 126 probands were seropositive for anti-nuclear autoantibody. In 20 probands, monitored before and serially after anti-Helicobacter therapy, seropositivity marked a severe hypokinetic response (p = 0.03). It may alert to continuing infection, even at low-density. Hyperhomocysteinemia is a risk factor for dementia and depression. Serum homocysteine exceeded the target in 43% of the 126 IP-probands. It was partially explained by serum B12 (12% variance, p < 0.001), but not by Helicobacter-status (gastric-atrophy uncommon in IP) or levodopa treatment. Immune-inflammatory activation increases homocysteine production. Since an estimated 60% of probands are hydrogen-breath-test positive, SIBO, with its increased bacterial utilisation of B12, is a likely cause. Thus, two prognostic indicators in established IP fit with involvement of Helicobacter and SIBO.

The Family Helicobacteraceae

“…Due to the chronic inflammatory nature of the H. pylori infection, it has been associated with some neurological conditions, including, Alzheimer's (Kountouras et al 2009) and Parkinson's (Charlett et al 2009) diseases, and ischemic heart disease (Longo-Mbenza 2009; Izadi et al 2012); however, currently there is insufficient data to prove a causal role for H. pylori in the pathophysiology of these diseases. Of interest however is a recent report, based on multiple logistic regression analysis, that showed that seropositivity to H. cinaedi, but not to H. pylori or Chlamydia pneumoniae, was an independent risk factor for atrial arrhythmia .…”

Towards Defining a Rigidity-Associated Pathogenic Pathway in Idiopathic Parkinsonism

“…Serum vitamin B 12 explained only 12% of the variance in homocysteine in IP, serum folate not contributing further [2] . Homocysteine was not related to Helicobacter infection: gastric atrophy is uncommon in IP.…”

“…Small intestinal bacterial overgrowth was found in two thirds of a group of probands and their spouses, the hydrogen breath test status being irrespective of the subject group [2] . Clouds of lysosomes are seen in duodenal enterocytes in relation to luminal bacteria [unpubl.…”

“…Our current hypothesis [2] is that 'the explanation of the different manifestations of IP between probands, and within proband over time, may lay in the interaction between more than one pathogen and determinants, genetic and environmental, of inflammatory response. Helicobacter may be necessary though not sufficient, SIBO [small intestinal bacterial overgrowth], a frequent, relatively non-specific and dose-related, player'.…”

“…Moreover, antinuclear antibody positivity marked a poorer response with apparently successful eradication, perhaps indicating persistence at 'low density'. This would fit with [2] : (a) prevalence of immunoblot seropositivity, anti-urease (enzyme-linked immunosorbent assay) seropositivity and urea breath test positivity in IP being 50, 35 and 30%, respectively. The cut-off points on the latter two (quantitative) tests may be too high to detect low density Helicobacter infection.…”