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

BACKGROUND: Following 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. METHODS: In 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. RESULTS: Of 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). CONCLUSION: We 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.

Differential effect of Helicobacter pylori eradication on time-trends in brady/hypokinesia and rigidity in idiopathic parkinsonism.

BACKGROUND: We examine the effect of eradicating Helicobacter in idiopathic parkinsonism (IP). Marked deterioration, where eradication-therapy failed, prompted an interim report in the first 20 probands to reach de-blinding. The null-hypothesis, "eradication has no effect on principal outcome, mean stride length at free-walking speed," was rejected. We report on study completion in all 30 who had commenced post-treatment assessments. METHODS: This is a randomized, placebo-controlled, parallel-group efficacy study of eradicating biopsy-proven (culture and/or organism on histopathology) Helicobacter pylori infection on the time course of facets of IP, in probands taking no, or stable long-t(1/2), anti-parkinsonian medication. Persistent infection at de-blinding (scheduled 1-year post-treatment) led to open active eradication-treatment. RESULTS: Stride length improved (73 (95% CI 14-131) mm/year, p = .01) in favor of "successful" blinded active over placebo, irrespective of anti-parkinsonian medication, and despite worsening upper limb flexor rigidity (237 (57-416) Nm x 10(-3)/year, p = .01). This differential effect was echoed following open active, post-placebo. Gait did not deteriorate in year 2 and 3 post-eradication. Anti-nuclear antibody was present in all four proven (two by molecular microbiology only) eradication failures. In the remainder, it marked poorer response during the year after eradication therapy, possibly indicating residual "low-density" infection. We illustrate the importance of eradicating low-density infection, detected only by molecular microbiology, in a proband not receiving anti-parkinsonian medication. Stride length improved (424 (379-468) mm for 15 months post-eradication, p = .001), correction of deficit continuing to 3.4 years. Flexor rigidity increased before hydrogen-breath-test positivity for small intestinal bacterial overgrowth (208 (28-388) Nm x 10(-3), p = .02), increased further during (171 (67-274), p = .001) (15-31 months), and decreased (136 (6-267), p = .04) after restoration of negativity (32-41 months). CONCLUSION: Helicobacter is an arbiter of progression, independent of infection-load.

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

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.

Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 2: response of facets of clinical idiopathic parkinsonism to Helicobacter pylori eradication. A randomized, double-blind, placebo-controlled efficacy study.

BACKGROUND: Links between etiology/pathogenesis of neuropsychiatric disease and infection are increasingly recognized. AIM: Proof-of-principle that infection contributes to idiopathic parkinsonism. METHODS: Randomized, double-blind, placebo-controlled efficacy study of proven Helicobacter pylori eradication on the time course of facets of parkinsonism. Intervention was 1 week's triple eradication therapy/placebos. Routine deblinding at 1 year (those still infected received open-active), with follow-up to 5 years post-eradication. Primary outcome was mean stride length at free-walking speed, sample size 56 for a difference, active vs. placebo, of 3/4 (between-subject standard deviation). Recruitment of subjects with idiopathic parkinsonism and H. pylori infection was stopped at 31, because of marked deterioration with eradication failure. Interim analysis was made in the 20 who had reached deblinding, seven of whom were receiving antiparkinsonian medication (long-t(1/2), evenly spaced) which remained unchanged. RESULTS: Improvement in stride-length, on active (n = 9) vs. placebo (11), exceeded size of effect on which the sample size was calculated when analyzed on intention-to-treat basis (p = .02), and on protocol analysis of six weekly assessments, including (p = .02) and excluding (p = .05) those on antiparkinsonian medication. Active eradication (blind or open) failed in 4/20, in whom B-lymphocyte count was lower. Their mean time course was: for stride-length, -243 (95% CI -427, -60) vs. 45 (-10, 100) mm/year in the remainder (p = .001); for the ratio, torque to extend to flex relaxed arm, 349 (146, 718) vs. 58 (27, 96)%/ year (p < .001); and for independently rated, visual-analog scale of stance-walk videos (worst-best per individual identical with 0-100 mm), -64 vs. -3 mm from anterior and -50 vs. 11 lateral (p = .004 and .02). CONCLUSIONS: Interim analysis points to a direct or surrogate (not necessarily unique) role of a particular infection in the pathogenesis of parkinsonism. With eradication failure, bolus release of antigen from killed bacteria could aggravate an effect of ongoing infection.