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.

Gait on a shoestring: falls and foot separation in parkinsonism.

A novel device for monitoring gait, which can be used in confined spaces, is described. In addition to distance/time assessment of gait, it measures foot separation whilst walking. A field trial illustrates its potential in the investigation of falls.

Reduced axial rotation in the spouses of sufferers from clinical idiopathic parkinsonism.

Axial rotation during recumbency was used to quantify the tendency towards parkinsonism with respect to one cardinal sign, brady/hypokinesia. Twenty-four elderly sufferers from idiopathic parkinsonism, their spouses, and 40 control subjects were studied. Significant differences in total angular displacement over 7 h were found between sufferers and their spouses (83% of grand mean) and between spouses of sufferers and controls (31%). These differences could not be accounted for by age or cognitive function. Moreover, the total angular displacement of the spouses was independent of whether they shared a bed with the sufferer. Neither the sufferers and their spouses, nor the 20 couples who constituted the control group, showed any relationship between partners with respect to angular displacement. These findings do not favour learned behaviour, or selective mating as an explanation of reduced movement in spouses of sufferers. Significantly more of the control couples had a single cardinal sign in both partners than expected on the basis of the frequency of a single sign in one partner. Environmental factors operating in adult life could be involved in the pathogenesis of parkinsonism.

Hypothesis: age-associated changes in gait represent, in part, a tendency towards parkinsonism.

In 144 healthy, active, asymptomatic volunteers (aged 30-88 years), age explained 33% of the variance in free walking speed. This could not be ascribed simply to differences in physique at maturity, since height had a more important effect on speed (p less than 0.0001) than did leg length (p less than 0.01). Multiple linear regression was used to fit models for speed, by selection from four sets of variables: common physical, body sway, functional anatomy of spine and lower limbs, and psychometric. The best model (which included age) explained little more of the variance (41%) than did age alone. Moreover, incorporation of age into the alternative model, built in its absence, still contributed significantly (p less than 0.0001) to the variance explained. The effect of age on gait appeared to be complex, with an increment in double support time disproportionate to the reduction in speed. We formulate by exclusion, the hypothesis that age-associated changes in gait represent, in part, a tendency towards parkinsonism.

Effect of captopril on functional, physiological and biochemical outcome criteria in aged heart failure patients.

1. Captopril was evaluated as an adjuvant to diuretic and digoxin therapy in heart failure in old age, using walking ability, minute ventilation and oxygen consumption and plasma atrial natriuretic factor (ANF) concentration as measures of outcome. 2. Twenty patients, mean (s.d.) age 81 (6) years, entered a double-blind, randomised, crossover study of three treatments, a twice daily regimen of captopril (AA), at a dosage established by titration against serum angiotensin converting enzyme (ACE) activity, the same dosage in the morning with placebo at night (AP), and twice daily placebo (PP). Each treatment lasted 3 weeks. A 2 week run-in period on triple therapy, with AA captopril, was used to assess stability and compliance. Seventeen completed all treatments: three completed two. 3. Any benefit of captopril was modest and there was deterioration in gait on the titrated dosage 3 months afterwards (P = 0.04). Efficacy in the old may be greatest when the titrated dose (25 or 50 mg) is given once daily: the multiple daily doses recommended may be unnecessarily demanding. 4. Walking performance was measured by gait analysis (GA) at free walking speed and by a simple walking test (SWT), in which patients stopped at the first relevant symptom. There was a consistent tendency for four measures of performance (GA: speed, stride length and double support time; SWT distance) to be best on the AP treatment, next best on AA, and worst on PP but for the fifth, SWT speed, AP and AA were similar. The trend appeared most marked for SWT distance, mean (s.e. mean) values for AP, AA and PP being 123 (15), 94 (16) and 75 (16) m, respectively. However, the treatment effect did not reach statistical significance at the 0.05 level. 5. There was no significant difference between treatments in minute ventilation, minute oxygen consumption, or their ratio, either at rest or on exercise. 6. Resting ANF concentrations were nearly four times higher (P = 0.0001) in the patients than those, mean (s.e. mean) 66 (5) pmol l-1, in eleven healthy volunteers of mean age 80 (6) years, and the increase on exercise, seen in the controls (P less than 0.01), was absent. In the patients the resting plasma ANF concentration was significantly affected by treatment (P = 0.03), being less on both AP, 245 (9), and AA, 214 (9) than on PP, 264 (10) pmol l-1 (P = 0.02 and 0.03, respectively). 7. Baseline serum ACE activity was induced on active treatment. The change in ACE activity at 3 h post an active dose was significantly greater on AP than AA (P = 0.005). The increased sensitivity to inhibition during once daily administration was reflected in mean arterial pressure. The pre-dose standing pressure was less on AP than on PP (P less than 0.05), and the change in postural fall (pre-dose minus 2 h post), was greater (P = 0.004), but AA and PP were similar in these respects.(ABSTRACT TRUNCATED AT 400 WORDS)

Objective evidence for tolerance, against a background of improvement, during maintenance therapy with controlled release levodopa/carbidopa.

We have investigated whether the potential benefits of a controlled release formulation of levodopa (200 mg)/carbidopa (50 mg), Sinemet CR, are realised during maintenance therapy. Eight sufferers from idiopathic Parkinsonism, mean age 69.9 y, were studied: all exhibited "end of dose" effect within 4 h of a dose of their maintenance therapy with levodopa (100 mg)/carbidopa (25 mg) in a conventional release formulation, Sinemet Plus. They received, in random order, initial single dose challenges with one tablet of Sinemet Plus, one and two tablets of Sinemet CR and placebo alone, each on a separate day. After a mean of 21 weeks on maintenance therapy with Sinemet CR, subsequent single dose challenges with Sinemet CR and placebo were made. Objective measures of performance and blood sampling for assay of plasma concentrations of levodopa and the major peripheral metabolite, 3-0-methyldopa (30MD) were carried out immediately before (10.00 h) and serially until 6 h after each challenge. The overall mean stride length was significantly greater in relation to the subsequent (679 mm) than the initial (517 mm) placebo challenge. Moreover, stride length immediately before the challenges was significantly greater on the subsequent occasions. Improved performance, also seen for free walking speed, was not explained by plasma levodopa or 30MD concentrations. In the initial challenges, the mean increment in stride length achieved by active treatment, as compared with placebo, did not differ significantly between the one (210 mm) and two (235 mm) tablet doses of Sinemet CR: a maximal response had been obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective outcome criteria in trials of anti-parkinsonian therapy in the elderly: sensitivity, specificity and reliability of measures of brady- and hypo-kinesia.

1. We compare the sensitivity and specificity of chosen outcome criteria in a placebo-controlled, randomised cross-over study of the efficacy of maintenance therapy with the levodopa/carbidopa combination (Sinemet Plus) alone. Patients were characterised by having idiopathic Parkinsonism with no overt fluctuations in control in relation to individual doses of medication. 2. The effect of omission of a morning dose of maintenance therapy on simple timed tests of mobility and manual dexterity, and on distance/time parameters of gait was studied in fourteen patients (aged 64 to 88 years). Measurements made 2, 4 and 6 h after morning active and placebo treatments were standardised by taking the pre-treatment measurement on that day as baseline. 3. In a linear model, which allowed for the structure of the study, neither the total time taken by each patient to get up from a chair, walk an individually set distance, turn, return to and sit in the chair, nor the rate of progress at fastening the same set of buttons, was sensitive to the treatment effect. 4. Three of the gait parameters, free walking speed, mean stride length and mean double support time, were sensitive to the treatment effect. Correction for the speed of each walk, caused some reduction in the sensitivity of stride length to treatment effect, but that of double support time remained. Speed, and double support time or stride length, appeared to be complementary in defining the treatment effect. 5. The linear modelling revealed the complexity of the treatment effect. Although active treatment, by comparison with placebo, increased free walking speed (P = 0.019), the more levodopa found in the plasma following treatment, (P = 0.0005) and the greater the increment in the concentration of its peripheral metabolite, 3-O-methyldopa (P = 0.006), the less the beneficial effect. This model may reflect reduced uptake into the brain and/or an adverse effect of parent drug or a metabolite. 6. The specificity of free walking speed for the treatment effect was good, as was that of mean stride length, after it had been corrected for speed of each walk, and of mean double support time, after correction for speed and incorporation of the change in lying blood pressure accompanying treatment into the model. 7. The measurements of gait parameters were ranked according to reliability.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of duration of levodopa/decarboxylase inhibitor therapy on the pharmacokinetic handling of levodopa in elderly patients with idiopathic Parkinson's disease.

We address, from a pharmacokinetic viewpoint, the important question of why some patients with clinical idiopathic Parkinson's disease experience a fall off in benefit from levodopa maintenance therapy. Thirteen such patients, of mean age 78 y, without overt fluctuations in motor control in temporal relation to dosing with a levodopa/decarboxylase inhibitor combination, were studied. Levodopa (currently 400 to 800 mg daily) had been started at between 61 and 81 y of age, the mean duration of therapy being 54 months. Plasma concentrations of levodopa and its peripheral metabolite, 3-0-methyldopa, were measured before a morning dose of levodopa (100 mg)/carbidopa (25 mg) and at hourly intervals for 6 h after. There was a significant negative regression between duration of levodopa therapy (but not age or severity of disease) and the area under the plasma concentration/time curve (AUC) for levodopa attributed to the test dose. A significant negative regression was also seen of duration of therapy on the dose absorbed per unit distribution volume, but not on the elimination rate constant, indicating a decrease in bioavailability and/or an increase in distribution volume with duration. There was a tendency for the plasma 3-0-methyldopa concentration, standardised for daily dose, [30MD], to increase with duration of therapy. Although, the regression of duration on [30MD] did not reach statistical significance, that on the ratio, [30 MD]/AUC, did so at the 0.01 level. The amount by, and time for which, the plasma levodopa concentration exceeds any critical threshold for the competitive active uptake process into the brain may thus decrease with duration of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of axial rotation: its relevance to screening for night-time hypokinesia in old age and parkinsonism.

A novel device for continuous monitoring of axial rotation of a recumbent person is described. It is self-applicable and small enough to be mailed. A field trial showed that parkinsonian patients change their position less frequently than did their spouses: the difference became smaller where the age of the spouse was equal to or greater than that of the sufferer. The most marked difference between sufferers and their spouses was with respect to total angular displacement, which was nearly four times greater in the spouses. Further work is needed to show whether impaired rotation predates clinical idiopathic Parkinson's disease and so acts as a useful predictor. Measurement of axial rotation seems valuable in judging risk of pressure sores and gauging improvement in mobility in response to therapeutic interventions.