<i>Helicobacter</i> Hypothesis for Idiopathic Parkinsonism: Before and Beyond

Dobbs, R. J.; Dobbs, S. M.; Weller, C.; Charlett, André; Bjarnason, Ingvar; Curry, Alan; Ellis, D. S.; Ibrahim, Merdol; McCrossan, Maria V.; O’Donohue, John; Owen, Robert J.; Oxlade, Norman L.; Price, Ashley B.; Sanderson, Jeremy; Sudhanva, Malur; Williams, John E.

doi:10.1111/j.1523-5378.2008.00622.x

Cited by 59 publications

(89 citation statements)

References 83 publications

(131 reference statements)

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“…Siblings of IP probands, living apart since childhood, exhibited a similar tendency towards parkinsonism as did probands' spouses [1] . However, siblings shared with probands an increased prevalence of Helicobacter anti-urease seropositivity, whereas spouses did not.…”

Section: Hypothesis For Aetiology/pathogenesis Of Ipmentioning

confidence: 78%

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Towards Defining a Rigidity-Associated Pathogenic Pathway in Idiopathic Parkinsonism

Dobbs¹,

Charlett

Dobbs³

et al. 2011

Neurodegener Dis

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Helicobacter pylori eradication has a differential effect on the facets of idiopathic parkinsonism (IP): brady/hypokinesia improves, but rigidity worsens. Small intestinal bacterial overgrowth is common in IP and has been described as a sequel to Helicobacter eradication. The hyperhomocysteinaemia of IP is, in part, explained by serum vitamin B₁₂, but the concentration is not explained by Helicobacter status. Moreover, Helicobacter-associated gastric atrophy is uncommon in IP. However, overgrowth both increases B₁₂ utilization and provides a source of inflammation to drive homocysteine production. It is not a bystander event in IP: clouds of lysosomes are seen in duodenal enterocytes. Its candidature for causality of a rigidity-associated pathway is circumstantial: there are biological gradients of rigidity on natural killer and T-helper blood counts, both being higher with hydrogen breath test positivity for overgrowth.

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Section: Hypothesis For Aetiology/pathogenesis Of Ipmentioning

confidence: 78%

“…To what might it be attributed? There was a fourfold increase in the odds of having abnormal bowel function in IP probands/spouses in the presence of an anti-urease-B immunoblot band, irrespective of the urea breath test status [1] . Specificity of this finding for IP needs investigation.…”

Section: Time Sequence In Response To Interventionmentioning

confidence: 89%

Towards Defining a Rigidity-Associated Pathogenic Pathway in Idiopathic Parkinsonism

Dobbs¹,

Charlett

Dobbs³

et al. 2011

Neurodegener Dis

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“…Long thin, often complex-branching, mitochondria are seen in duodenal enterocytes [14], rather than the protein arrays encapsulated by a double-membrane associated with H . pylori [12].…”

Section: Introductionmentioning

confidence: 99%

Leukocyte-subset counts in idiopathic parkinsonism provide clues to a pathogenic pathway involving small intestinal bacterial overgrowth. A surveillance study

et al. 2012

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BackgroundFollowing Helicobacter pylori eradication in idiopathic parkinsonism (IP), hypokinesia improved but flexor-rigidity increased. Small intestinal bacterial-overgrowth (SIBO) is a candidate driver of the rigidity: hydrogen-breath-test-positivity is common in IP and case histories suggest that Helicobacter keeps SIBO at bay.MethodsIn a surveillance study, we explore relationships of IP-facets to peripheral immune/inflammatory-activation, in light of presence/absence of Helicobacter infection (urea-breath- and/or stool-antigen-test: positivity confirmed by gastric-biopsy) and hydrogen-breath-test status for SIBO (positivity: >20 ppm increment, 2 consecutive 15-min readings, within 2h of 25G lactulose). We question whether any relationships found between facets and blood leukocyte subset counts stand in patients free from anti-parkinsonian drugs, and are robust enough to defy fluctuations in performance consequent on short t½ therapy.ResultsOf 51 IP-probands, 36 had current or past Helicobacter infection on entry, 25 having undergone successful eradication (median 3.4 years before). Thirty-four were hydrogen-breath-test-positive initially, 42 at sometime (343 tests) during surveillance (2.8 years). Hydrogen-breath-test-positivity was associated inversely with Helicobacter-positivity (OR 0.20 (95% CI 0.04, 0.99), p<0.05).In 38 patients (untreated (17) or on stable long-t½ IP-medication), the higher the natural-killer count, the shorter stride, slower gait and greater flexor-rigidity (by mean 49 (14, 85) mm, 54 (3, 104) mm.s-1, 89 (2, 177) Nm.10-3, per 100 cells.μl-1 increment, p=0.007, 0.04 & 0.04 respectively, adjusted for patient characteristics). T-helper count was inversely associated with flexor-rigidity before (p=0.01) and after adjustment for natural-killer count (-36(-63, -10) Nm.10-3 per 100 cells.μl-1, p=0.007). Neutrophil count was inversely associated with tremor (visual analogue scale, p=0.01). Effect-sizes were independent of IP-medication, and not masked by including 13 patients receiving levodopa (except natural-killer count on flexor-rigidity). Cellular associations held after allowing for potentially confounding effect of hydrogen-breath-test or Helicobacter status. Moreover, additional reduction in stride and speed (68 (24, 112) mm & 103 (38, 168) mm.s-1, each p=0.002) was seen with Helicobacter-positivity. Hydrogen-breath-test-positivity, itself, was associated with higher natural-killer and T-helper counts, lower neutrophils (p=0.005, 0.02 & 0.008).ConclusionWe propose a rigidity-associated subordinate pathway, flagged by a higher natural-killer count, tempered by a higher T-helper, against which Helicobacter protects by keeping SIBO at bay.

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“…In IP, there is no convincing evidence of excessive exposure to xenobiotics, or of the relevance of genes regulating their metabolism [18]. There is no indication of malnutrition/malabsorption, but increased energy expenditure may cause weight loss [24].…”

Section: Introductionmentioning

confidence: 99%

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

Charlett

Dobbs

et al. 2009

Gut Pathog

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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.

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Helicobacter Hypothesis for Idiopathic Parkinsonism: Before and Beyond

Cited by 59 publications

References 83 publications

Towards Defining a Rigidity-Associated Pathogenic Pathway in Idiopathic Parkinsonism

Towards Defining a Rigidity-Associated Pathogenic Pathway in Idiopathic Parkinsonism

Leukocyte-subset counts in idiopathic parkinsonism provide clues to a pathogenic pathway involving small intestinal bacterial overgrowth. A surveillance study

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

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