Significantly higher frequency of Helicobacter suis in patients with idiopathic parkinsonism than in control patients.

BACKGROUND: There is increased proportional mortality from Parkinson's disease amongst livestock farmers. The hypokinesia of Parkinson's disease has been linked to Helicobacter pylori. H. suis is the most common zoonotic helicobacter in man. AIM: To compare the frequency of H. suis, relative to H. pylori, in gastric biopsies of patients with idiopathic parkinsonism (IP) and controls from gastroenterology services. METHODS: DNA extracts, archived at a Helicobacter Reference Laboratory, from IP patient and gastroenterology service biopsies were examined anonymously for H. suis, using species-specific RT-PCR. RESULTS: Relative risk of having H. suis in 60 IP patients compared with 256 controls was 10 times greater than that of having H. pylori. In patients with IP and controls, respectively, frequencies of H. suis were 27 (exact binomial 95% C.I. 15, 38) and 2 (0, 3)%, and of H. pylori, 28 (17, 40) and 16 (12, 21)%. Excess of H. suis in IP held when only the antral or corporal biopsy was considered. Of 16 IP patients with H. suis, 11 were from 19 with proven H. pylori eradication, 3 from 17 pre-H. pylori eradication, 2 from 24 H. pylori culture/PCR-negative. Frequency was different between groups (P = 0.001), greatest where H. pylori had been eradicated. Even without known exposure to anti-H. pylori therapy, H. suis was more frequent in IP patients (5/41) than in controls (1/155) (P = 0.002). Partial multilocus sequence typing confirmed that strains from IP patients (6) and control (1) differed from RT-PCR standard strain. CONCLUSIONS: Greater frequency of H. suis in idiopathic parkinsonism appears exaggerated following H. pylori eradication. Multilocus sequence testing comparison with porcine strains may clarify whether transmission is from pigs/porcine products or of human-adapted, H. suis-like, bacteria.

Downward shift in serum IgM with Helicobacter pylori seropositivity.

OBJECTIVE: To determine whether Helicobacter pylori infection is associated with premature immune ageing, with respect to circulating immunoglobulins. METHODS: Serum immunoglobulin classes and H. pylori anti-urease antibody were measured in 205 subjects (aged 30-89 years), obeying inclusion/exclusion criteria. RESULTS: IgM decreased (P<0.001) by 0.9 (95% C.I. 0.3, 1.4)% per year, H. pylori seropositivity having an effect equivalent to 25 years of ageing (P<0.02). IgA increased by 0.5 (0.1, 0.8)% per year (P<0.007), IgG being unaffected by age. Seropositivity had no effect on IgA or IgG. CONCLUSIONS: Increasing age and H. pylori seropositivity are each associated with a downward shift in circulating IgM. If clinical extrapolation is justified, H. pylori eradication may be important in combating susceptibility to infection in old age.

Parkinsonism: differential age-trend in Helicobacter pylori antibody.

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.

Link between Helicobacter pylori infection and idiopathic parkinsonism.

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.

Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism.

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.

Parkinsonism: siblings share Helicobacter pylori seropositivity and facets of syndrome.

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.

Cortisol is higher in parkinsonism and associated with gait deficit.

INTRODUCTION: We propose an active pathogenic mechanism, involving circulating cortisol, in parkinsonism. MATERIALS AND METHODS: Serum cortisol was measured in 96 subjects with idiopathic parkinsonism, 170 without, and in 17 spouses and 36 siblings of elderly sufferers with double the number of controls, all obeying inclusion/exclusion criteria. RESULTS: Cortisol, adjusted for sampling time, was greater (17%, on average, P<0.001) in parkinsonians, but not in relatives. The central cortisol lowering effect of anti-muscarinics was seen (P=0.025). Selegiline may attenuate the disease, and parkinsonism is less frequent in tobacco smokers. Selegiline was associated with a lower cortisol (P=0.03): chronic smoking appeared (P=0.08) to be, irrespective of parkinsonism. Bowel stasis has been implicated in the pathogenesis: cortisol was higher in parkinsonians requiring laxatives (P=0.05). In controls, cortisol was lower, the longer the stride (P=0.02): in parkinsonians, this relationship was numerically reversed. A similar (P=0.01) group performance interaction was seen for deterioration, over 4 years, in gait. CONCLUSION: Cortisol is doing harm or mirroring something which is. A common pathway for neuronal protection/rescue emerges.

Breadth of base whilst walking: effect of ageing and parkinsonism.

BACKGROUND: The effect of healthy ageing and of parkinsonism on breadth of base whilst walking had not been adequately documented. DESIGN: Height-specific reference ranges for mean foot separation at mid-swing were derived for males and females, age not proving to be a significant influence. METHOD: Normative data were obtained from 164 healthy volunteers, and foot separation in idiopathic parkinsonism (99 patients) was characterized by comparison. RESULTS: Parkinsonism was associated with significantly greater within- and between-subject variability in foot separation. There was a linear trend from increased separation in those with bilateral signs but little functional impairment, to decreased separation in the severely impaired but not yet chair or bed bound. Foot separation was best explained by two clinical signs, rigidity and anatomical postural abnormality. A flexed posture was associated with increased separation, rigidity with decreased, the separation manifested being determined by the net effect. CONCLUSION: In early idiopathic parkinsonism, falling may depend on abnormal posture, and increased breadth of base be compensatory. Later, the decrement in foot separation may become a primary determinant of falls.

Objective measurement of activation of rigidity: diagnostic, pathogenetic and therapeutic implications in parkinsonism.

1. Quantification of the effect on rigidity of its 'activation', by isometric grip, of standardized pressure, of the contralateral hand, was explored. Torque required to move the forearm through a fixed angle of 40 degrees, at a controlled rate of 0.5 Hz, in a horizontal plane about a pivotal axis aligned to the elbow joint, was recorded before (12 'baseline' recordings), during (10), and after (> or = 8) activation. Work required per unit displacement was calculated. 2. Specificity: Pilot serial daytime measurements gave an overall mean ratio, work required on activation over baseline, of 2.94 (95% CI 2.53, 3.42) in two elderly untreated parkinsonians, and 3.19 (2.75, 3.71) in two elderly subjects with isolated, clinically activation phenomenon, compared with 1.90 (1.64, 2.21) in two elderly without (P < 0.001), whilst two young adults did not activate, 0.98 (0.85, 1.14). In elderly subjects, work required under activation decreased during the day in health (-10 (-5, -14)% h-1, P = 0.0002), showed no significant change in those with clinical activation (4 (-1, 9)% h-1), and increased in parkinsonians (6 (0, 12)% h-1, P = 0.05): there appeared to be a transitionary state. 3. Validation of methodology: Quantifying the same work ratio on a single occasion in 20 aged parkinsonians (P), their spouses (Ps), 20 index controls (C) without parkinsonism, matched to (P), and their spouses (Cs) gave corroborative evidence of a pre-clinical state, defined by other measurements, in the spouses of sufferers. Values for C, Cs and Ps, 1.89 (1.42, 2.52), 2.38 (1.79, 3.17) and 2.93 (2.20, 3.90) respectively, were in consecutive positions, from health to (P, 2.96 (2.22, 3.95)) disease (P = 0.001 for Ps c.f. C; P = 0.1 for Ps c.f. Cs). Data on change over the day may enhance discrimination. 4. Sensitivity to medicines was illustrated, in two parkinsonians, by randomised, placebo balanced and controlled challenges: 1 and 2 tablets, Sinemet CR (Du Pont Pharmaceuticals, each levodopa 200 mg/carbidopa 50 mg) and 1 tablet, Sinemet-Plus (levodopa 100 mg/carbidopa 25 mg), then two 2 mg tablets, benzhexol. The dopaminergic effect (P < 0.001) was selective for activation (treatment.test-condition interaction, P = 0.004), and showed the expected time profiles. The effect of benzhexol (P = 0.008) lacked such selectivity. Its onset (> 4, < or = 6 h) was delayed, compatible with a gastrointestinal anti-muscarinic action and the subjects' ages. 5. Reliability (Fleiss's criterion) was shown to be good in 30 untreated parkinsonians.

Time course of physical and psychological responses to selegiline monotherapy in newly diagnosed, idiopathic parkinsonism.

RATIONALE: Poor specificity of face-value endpoints and the poor sensitivity of gross clinical examination may have militated against demonstrating prophylaxis by selegiline. METHODS: Objective measures of the four cardinal signs were used as primary outcome criteria in a randomised, double-blind, placebo-controlled, parallel group study of selegiline monotherapy in 25 newly diagnosed elderly sufferers from idiopathic parkinsonism, stratified for sex and Hoehn and Yahr functional staging. RESULTS: There was a significant interaction between time and nature of treatment with respect to rigidity. The effect of time during active treatment was highly significant: rigidity decreased by 1.3% per week. The worsening of rigidity on placebo was not statistically significant. Neuronal rescue is a possible explanation for the long term, progressive improvement produced by selegiline. No significant treatment effect was seen on the other cardinal signs. However, there was a significant quadratic time trend for arousal on active treatment suggesting tolerance to this effect. CONCLUSION: The difference in time course between the psychostimulant and physical effects suggests more than one mode of action.

Could seborrhoeic dermatitis be implicated in the pathogenesis of parkinsonism?

The spouses of a group of aged sufferers have been demonstrated to have multifarious differences relevant to parkinsonism from matched controls, which were difficult to explain by selective mating, learned or reactive behaviour. Could parkinsonism be transmissible? The frequency of inflammation and scaling on head or neck was greater (P = 0.05) in these spouses (19 available) than in controls (36), the best discriminating site of inflammation being scalp (P = 0.02). Both seborrhoeic dermatitis and overt, or pre-clinical, parkinsonism occurred in sufferers and spouses: to presume they are not causally related is to accept multiple entities. In favour of seborrhoeic dermatitis being causal for parkinsonism, rather than vice versa, is the involvement of a known organism, Pityrosporum ovale, in the dermatitis, and that the evidence of parkinsonism in the spouses indicated that they were only part way down the path towards the clinical condition.

Defining small differences in efficacy between anti-parkinsonian agents using gait analysis: a comparison of two controlled release formulations of levodopa/decarboxylase inhibitor.

1. Stride length is highly relevant to mobility and is sensitive to the effects of levodopa in Parkinsonism. Its selection as the primary outcome criterion allowed comparison of two levodopa/decarboxylase inhibitor formulations using a small number of subjects. 2. It is also desirable to improve stability. An instrumental method, based on infrared telemetry, has been developed which obtains both distance/time measures of gait and broadness of base, as measured by foot separation at mid-swing. The latter was used as a subsidiary outcome criterion. 3. Nine patients (aged 57 to 77 years) then receiving maintenance therapy for idiopathic Parkinsonism with Sinemet CR alone, but who had previously experienced end of dose effect within 4 h of receiving a dose of a conventional formulation of levodopa/decarboxylase inhibitor, were studied. 4. They received, in random order and at least 4 days apart, single doses of one tablet of Sinemet CR (200 mg levodopa/50 mg carbidopa) and of two capsules of Madopar CR (each 100 mg levodopa/25 mg benserazide), with placebo balance, at 10.00 h. Gait analysis was carried out immediately before and half-hourly for 7 h after a challenge. No routine doses of Sinemet CR were taken between 22.00 h on the night before and 17.00 h on the day of a challenge. 5. Analysis of variance showed a highly significant difference in mean stride length (P < 0.001) and in mean foot separation (P = 0.01) between serial time points, irrespective of the nature of treatment. There appeared to be a useful therapeutic response to both challenges.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothesis: the bradyphrenia of parkinsonism is a nosological entity.

Reaction time was studied in 103 subjects with idiopathic parkinsonism and 144 without. Central processing time, as measured by the response to a warning, had a component which could be explained by the presence or absence of parkinsonism, but not by the ageing process, a mental test score, or consumption of exogenous substances. Depression did not influence the efficiency of response. Cigarette smoking and anti-parkinsonian medication were associated with greater efficiency.

Assessment of the bradyphrenia of parkinsonism: a novel use of delayed auditory feedback.

Sufferers from parkinsonism have difficulty shifting or developing an appropriate mental set. Delayed auditory feedback may, therefore, disrupt their speech more than that of healthy controls. This was the case when 104 subjects with idiopathic parkinsonism and 144 without were compared. Moreover, the disruptive effect was complementary, in discriminating between those with and without clinical parkinsonism, to the response in reaction time to a warning. Unlike the latter, the disruption caused by delayed auditory feedback appeared independent of mental test score results and uninfluenced by consumption of tobacco or anti-parkinsonian therapy. Neither were influenced by a rating of affect. More precise delineation of the mental disorders of parkinsonism is needed in clinical practice, set against background information on prognosis and drug responsiveness.

Quantification of the cardinal signs of parkinsonism and of associated disability in spouses of sufferers.

Work on the causation of idiopathic parkinsonism is limited by relying on gross clinical definition and lack of studies in the old. A prognostic index for parkinsonism, based on hypo/bradykinesia of gait, had considerably higher values in spouses of 20 aged suffers, who had been cohabiting for about half a century, than in 40 controls. Postural abnormality, measured by standing sway and foot separation during walking, was also greater in these spouses. Marked differences remained after correction for relevant covariates. A blinded rigidity rating was greater in the spouses of sufferers, tremor rating was not. The differences found are difficult to explain by selective mating, learned or reactive behaviour. This suggests that environmental causative influences operate in adult life.

Gait in relation to ageing and idiopathic parkinsonism.

Distance/time measures of gait in 105 sufferers from idiopathic Parkinsonism, who were able to walk unaided, and 144 healthy controls were examined systematically. Those sufferers with overt fluctuations in control were assessed during their "therapeutic window". Free walking speed was lower for a given cadence in the sufferers, but reached a plateau whilst cadence could still be increased. Age, cognitive function and the range of passive hip flexion were important determinants of gait in them. Even minor degrees of cognitive impairment were associated with reduced free walking speed in sufferers: it appears unwise that they were prescribed more sedatives than the controls. The potential benefit of physiotherapy in maintaining joint flexibility was noted. The deficits in speed of individual sufferers, and hence the estimated potential for prophylaxis and treatment, were unrelated to age at presentation. There was no evidence for a limited period of responsiveness to levodopa therapy in this cross-sectional study.