Parkinson Disease: Oxlade NL

Dobbs RJ, Dobbs SM, Weller C, Charlett A, Bjarnason IT, Curry A, Ellis DS, Ibrahim MA, McCrossan MV, O'Donohue J, Owen RJ, Oxlade NL, Price AB, Sanderson JD, Sudhanva M, Williams J. · Section of Clinical Neuropharmacology, Institute of Psychiatry, King's College London, London, UK. or · Helicobacter. · Pubmed #19250506 No free full text.

Abstract: We challenge the concept of idiopathic parkinsonism (IP) as inevitably progressive neurodegeneration, proposing a natural history of sequential microbial insults with predisposing host response. Proof-of-principle that infection can contribute to IP was provided by case studies and a placebo-controlled efficacy study of Helicobacter eradication. "Malignant" IP appears converted to "benign", but marked deterioration accompanies failure. Similar benefit on brady/hypokinesia from eradicating "low-density" infection favors autoimmunity. Although a minority of UK probands are urea breath test positive for Helicobacter, the predicted probability of having the parkinsonian label depends on the serum H. pylori antibody profile, with clinically relevant gradients between this "discriminant index" and disease burden and progression. In IP, H. pylori antibodies discriminate for persistently abnormal bowel function, and specific abnormal duodenal enterocyte mitochondrial morphology is described in relation to H. pylori infection. Slow intestinal transit manifests as constipation from the prodrome. Diarrhea may flag secondary small-intestinal bacterial overgrowth. This, coupled with genetically determined intense inflammatory response, might explain evolution from brady/hypokinetic to rigidity-predominant parkinsonism.

Bjarnason IT, Bjarnason IT, Charlett A, Dobbs RJ, Dobbs SM, Ibrahim MA, Kerwin RW, Mahler RF, Oxlade NL, Peterson DW, Plant JM, Price AB, Weller C. · Section of Neuropharmacology, Institute of Psychiatry, London, UK. · Helicobacter. · Pubmed #16104943 No free full text.

Abstract: 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.

Weller C, Charlett A, Oxlade NL, Dobbs SM, Dobbs RJ, Peterson DW, Bjarnason IT. · Section of Clinical Neuropharmacology, Institute of Psychiatry, London, UK. · Helicobacter. · Pubmed #16104944 No free full text.

Abstract: BACKGROUND: Eradicating Helicobacter may convert rapidly progressive idiopathic parkinsonism to quieter disease, however only a minority of probands have evidence of current infection. AIM: To explore the cross-sectional fit of parkinsonism as an extra-alimentary consequence of Helicobacter pylori, using the serum antibody profile. METHODS: A discriminant index for parkinsonism was based on the Western Blot pattern of IgG antibodies against electrophoretically separated H. pylori antigens in 124 subjects with idiopathic parkinsonism, 196 without. In parkinsonism, association was assessed between index and 1, anthropometric measures; 2, current and 3, increase over 4 years in hypokinetic and psychomotor/psychometric disability; and 4, a global score of current severity. RESULTS: Predicted probability of being labeled parkinsonian was greatest with cytotoxin-associated-gene-product (CagA) positivity and vacuolating-toxin negativity (p = .03 and .004, respectively, for antibody-age interactions), and urease-B negativity (p = .03, irrespective of age). In this circumstance, the odds for parkinsonism increased fivefold by age 80 years (p = .001). Helicobacter status, according to anti-urease enzyme-linked immunosorbent assay (ELISA), did not complement the model. Gradients, of clinically relevant size, were found between index and disease burden, despite the potentially confounding effect of antiparkinsonian medication. The higher the index 1, the worse was posture, as gauged by forward displacement of occiput (p = .04), 2, the shorter mean stride-length (p = .003), longer reaction time (= .002) and lesser cognitive efficiency (= .03), 3, the greater their deterioration (p = .006, .002, and .03 respectively), and 4, the greater the overall severity of parkinsonism (< .001). CONCLUSION: The apparent importance of H. pylori in the etiology/pathogenesis of idiopathic parkinsonism is not confined to those with evidence of current infection.

Dobbs RJ, Dobbs SM, Weller C, Bjarnason IT, Bjarnason IT, Oxlade NL, Charlett A, Al-Janabi MA, Kerwin RW, Mahler RF, Price AB. · Section of Clinical Neuropharmacology, Institute of Psychiatry, London, UK. · Helicobacter. · Pubmed #16104942 No free full text.

Abstract: BACKGROUND: Neuronal damage in idiopathic parkinsonism may be in response to ubiquitous occult infection. Since peptic ulceration is prodromal, Helicobacter is a prime candidate. AIM: To consider the candidature of Helicobacter in parkinsonism with cachexia. METHODS: We explore the relationship between being underweight and inflammatory products in 124 subjects with idiopathic parkinsonism and 195 controls, and present the first case-series evidence of efficacy of Helicobacter eradication, in parkinsonism advanced to the stage of cachexia. RESULTS: Association of a low body mass index with circulating interleukin-6 was specific to parkinsonism (p = .002), unlike that with antibodies against Helicobacter vacuolating-toxin and cytotoxicity-associated gene product (p < .04). Marked reversibility in both cachexia and disability of idiopathic parkinsonism followed Helicobacter heilmannii eradication in one case, Helicobacter pylori eradication in another, follow-up being > or = 3.5 years. The latter presented with postprandial bloating, and persistent nausea: following eradication, radioisotope gastric-emptying returned towards normal, and upper abdominal symptoms regressed. Reversibility of their cachexia/disability contrasts with the outcome of anti-Helicobacter therapy where eradication repeatedly failed (one case), and in non-Helicobacter gastritis (three cases). Anti-parkinsonian medication remained constant. Intestinal absorption and barrier function were normal in all. CONCLUSION: Categorization, according to presence or absence of Helicobacter infection, was a useful therapeutic tool in late idiopathic parkinsonism.