Parkinson Disease: Charlett A

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.

Weller C, Oxlade N, Dobbs SM, Dobbs RJ, Charlett A, Bjarnason IT. · Section of Clinical Neuropharmacology, Institute of Psychiatry, King's College, London SE5 8AF, UK. · FEMS Immunol Med Microbiol. · Pubmed #15866206 No free full text.

Abstract: Idiopathic parkinsonism (IP) is a common disorder, conventionally regarded as neurodegenerative. Its cardinal features, poverty and slowness of movement, muscle rigidity, postural abnormality and a characteristic tremor, are associated with loss of dopaminergic neurones in the substantia nigra of the brain. Genetic factors explain only a minority of cases, and a common toxic environmental insult remains elusive. We propose that IP is a systemic disorder resulting from a ubiquitous peripheral infection, and that only the tip of the iceberg comes to diagnosis. There is evidence for inflammatory/immune activation peripherally and in the brain. We have used statistical modelling to explore links with non-specific and specific systemic markers of inflammation/infection in IP probands, and explore whether their partners and siblings have a frank or pre-presentation parkinsonian state. Critical to this approach is continuous objective measures of the facets of IP. Hypotheses on causality and mechanism are based on the statistical models. There is pathological and clinical evidence for direct involvement of the gastrointestinal tract in IP. The candidacy of Helicobacter pylori infection as a trigger event or driving infection is relatively high. We have found that eliminating infection in late parkinsonism with cachexia, a stage usually considered intractable, can result in a U-turn. However, eradication therapy may not provide a complete solution. Persistence of antibody against cytotoxin-associated antigen (CagA), increases the predicted probability of being labelled as having parkinsonism. Evidence for autoimmunity and immunocompromise is used to build schemes for the natural history. We conclude that current classifications of neuropsychiatric disease may not prove the best with respect to defining sub-clinical disease, prophylaxis or halting progression.

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.

Dobbs RJ, Charlett A, Dobbs SM, Weller C, Peterson DW. · Therapeutics in the Elderly, Research Group, Northwick Park and St Mark's Hospitals, Harrow, UK. · Aliment Pharmacol Ther. · Pubmed #10971237 links to  free full text

Abstract: BACKGROUND: Parkinsonism is associated with prodromal peptic ulceration. Dopamine antagonists provoke experimental ulcer, dopaminergic agents protect, and might inhibit growth of Helicobacter pylori. OBJECTIVE: To describe the relationship between H. pylori serology and parkinsonism. METHODS: Serum H. pylori anti-urease-IgG antibody was measured in 105 people with (idiopathic) parkinsonism, 210 without, from same locality. None had received specific eradication therapy. RESULTS: Controls showed a birth-cohort effect: antibody titre rose from 30 to 90 years (P < 0. 001). Parkinsonism obliterated this (disease status. age interaction, P < 0.05), the differential age trend not being attributable to social class. Those with diagnosed parkinsonism were more likely to be seropositive (odds ratio 2.04 (95% CI: 1.04, 4.22) P < 0.04) before 72.5 years. Overall, titre fell (P=0.01) by 5 (1, 9)% per unit increase in a global, 30-point rating (median 14 (interquartile range 10.5, 17)) of disease severity. No individual category of anti-parkinsonian medication (92% taking) had a differential lowering effect. CONCLUSIONS: Higher prevalence of seropositivity in parkinsonism, before 8th decade, may be due to host susceptibility/reaction, or, conversely, infection with particular H. pylori strain(s) lowering dopaminergic status. Absence of a birth cohort effect in parkinsonism, despite similar social class representation, may be consequent on eradication, spontaneous (gastric atrophy) or by anti-parkinsonian medication.

Dobbs SM, Dobbs RJ, Weller C, Charlett A. · Therapeutics in the Elderly, Research Group, Northwick Park & St Mark's Hospitals, Harrow, UK. · Med Hypotheses. · Pubmed #10904422 No free full text.

Abstract: The conventional concept for an environmental cause of idiopathic parkinsonism is an insult (e.g. neurotoxin or encephalitis), superimposed on age-related attrition of nigral dopaminergic neurons, and temporally remote from neurological diagnosis. To the contrary, we describe the fit of Helicobacter pylori. This commonest of known bacterial infections, usually acquired in childhood, persists, and has been linked with peptic ulcer/non-ulcer dyspepsia, immunosuppression and autoimmunity. Acquired immunosuppression, predisposing to auto-immunity, is assessed as a model for the pathogenesis of parkinsonism and parkinsonian-like attributes of ageing. Eradication of a trigger has potential to change the approach to parkinsonism, just as it did to peptic ulcer. The tenet of inevitable age-related attrition of dopaminergic neurons may also require revision.

Dobbs RJ, Charlett A, Purkiss AG, Dobbs SM, Weller C, Peterson DW. · Therapeutics in the Elderly, Research Group, The Hillingdon Hospital Postgraduate and Research Centre, Uxbridge, Hatfield, Hertfordshire, UK. · Acta Neurol Scand. · Pubmed #10416510 No free full text.

Abstract: INTRODUCTION: We propose that the increase in TNF-alpha and IL-6 in the brain in idiopathic parkinsonism is in response to a peripheral immune/ inflammatory process, so ubiquitous as to be responsible for the resemblance between ageing and parkinsonism. METHODS: Circulating cytokine was measured in 78 subjects with idiopathic parkinsonism and 140 without, aged 30 to 90 years, all obeying inclusion/exclusion criteria. RESULTS: Serum TNF-alpha increased (P<0.0001) by 1.37 (95% CI 0.75, 2.00)% x y(-1), IL-6 by 2.63 (1.75, 3.52) (P<0.0005). TNF-alpha appeared elevated in parkinsonians whose postural and psychomotor responses were abnormal, being suppressed where they were normal: trends which contrasted with those in controls (P = 0.015 and 0.05, respectively). Parkinsonism appeared (P = 0.08) to have an effect on IL-6, equivalent to that of >10 years of ageing (28(-3, 69)%), but was not immediately related to between-subject differences in performance. CONCLUSION: Ageing and pathogenetic insult may be confounded, age being a progression, not a risk, factor.

Charlett A, Dobbs RJ, Dobbs SM, Weller C, Brady P, Peterson DW. · Therapeutics in the Elderly, Research Group, The Hillingdon Hospital Postgraduate and Research Centre, Uxbridge, UK. · Acta Neurol Scand. · Pubmed #9925235 No free full text.

Abstract: OBJECTIVE: Given a history of peptic ulcer is more frequent in parkinsonism, to investigate the role of Helicobacter pylori in its pathogenesis and of cross-infection in familial aggregation. METHODS: Facets of parkinsonism were quantified in 33 elderly subjects with idiopathic parkinsonism and in their 39 siblings with double the number of controls, all obeying inclusion/exclusion criteria. Specific-IgG antibody was assayed. RESULTS: Siblings, compared with controls, had brady/hypokinesia of gait (P< or =0.002), bradykinesia of hands (P = 0.01), abnormal posture (P = 0.001), rigidity (P < 0.001) and seborrhoea/seborrhoeic dermatitis (P = 0.02). Both parkinsonians and siblings differed from controls in the odds of being H. pylori seropositive [odds ratios 3.04 (95% C.I.: 1.22, 7.63) and 2.94 (1.26, 6.86) respectively, P < 0.02], seropositivity being found in 0.70 of sufferers. CONCLUSION: Familial transmission of chronic infection plus part of syndrome links Helicobacter with causality. Seropositivity not being universal throughout parkinsonism, consequent on gastric atrophy +/- sporadic antibiotic exposure, might explain less aggressive disease in older sufferers.