RESUMEN
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.
Asunto(s)
Infecciones por Helicobacter/tratamiento farmacológico , Enfermedad de Parkinson/microbiología , Adulto , Anciano , Antibacterianos/uso terapéutico , Antiulcerosos/uso terapéutico , Quimioterapia Combinada , Femenino , Marcha/efectos de los fármacos , Infecciones por Helicobacter/microbiología , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/genética , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Infecciones por Helicobacter/complicaciones , Enfermedad de Parkinson/etiología , Animales , Humanos , Mitocondrias/patología , Mitocondrias/ultraestructura , Modelos Biológicos , Enfermedad de Parkinson/microbiología , Enfermedad de Parkinson/patologíaRESUMEN
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.
RESUMEN
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.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/inmunología , Enfermedad de Parkinson/etiología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Femenino , Enfermedades Gastrointestinales/inmunología , Enfermedades Gastrointestinales/microbiología , Infecciones por Helicobacter/inmunología , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/microbiología , Enfermedad de Parkinson/fisiopatología , Valor Predictivo de las Pruebas , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
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.
Asunto(s)
Antibacterianos/uso terapéutico , Caquexia/etiología , Caquexia/microbiología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Inflamación/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/microbiología , Anciano , Caquexia/tratamiento farmacológico , Caquexia/fisiopatología , Enfermedad Crónica , Femenino , Infecciones por Helicobacter/inmunología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Resultado del TratamientoRESUMEN
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.