Familial occurrence of Parkinson's disease in a community-based case-control study.

Purpose: To study the occurrence of Parkinson's disease (PD) in the relatives of parkinsonian patients (n=119), and of their matched controls (n=238).Scope: More patients reported a positive family history of PD in their first degree relatives, compared to their controls (OR 2.7, 95% CI 1.3-5.9), and the incidence of PD among those relatives was also significantly higher (OR 1.4, 95% CI 1.1-1.8).Conclusions: Familial occurrence of PD is not necessarily a sign of genetic mechanisms in the etiology of PD. Shared environment with common risk factors might be even more important.

Detection of response to COMT inhibition in FDOPA PET in advanced Parkinson's disease requires prolonged imaging.

The aim was to investigate whether the improved 6-[(18)F]fluoro-L-dopa (FDOPA) availability induced by catechol-O-methyltransferase (COMT) inhibition can be more clearly seen during late than during standard (early) imaging in FDOPA uptake in Parkinson's disease (PD) patients with severe dopaminergic hypofunction. Six PD patients and six healthy controls were investigated up to 3.5 h after FDOPA injection with and without a single 400-mg dose of a peripheral COMT inhibitor, entacapone. Prolonged (late) imaging showed a significantly higher increase in FDOPA uptake than standard 1.5 h (early) imaging after entacapone both in controls and in PD patients. The increase in the (putamen-occipital):occipital ratios was 37.4% during early and 70.4% during late imaging in controls. In PD patients, there was no significant change in the ratios during early imaging, but the late imaging showed a significant increase in the putamen-to-occipital ratio of 54.2% after COMT inhibition. Late imaging reveals more clearly the prolonged FDOPA availability induced by COMT inhibition leading to higher cumulated striatal activity compared with early imaging. This might be worth considering in FDOPA studies, especially if investigations are planned to do without blood sampling. Late imaging shows the storing potential of FDA better than is seen during early FDOPA PET imaging after entacapone administration. In patients with severe presynaptic dopaminergic hypofunction, its detection requires prolonged imaging.

Risk for Parkinson's disease: twin studies for the detection of asymptomatic subjects using [18F]6-fluorodopa PET.

Positron emission tomography (PET) studies were carried out with [18F]6-fluorodopa ([18F]6-FD) in monozygotic (MZ) and dizygotic (DZ) twins for the clarification of dopaminergic function. Four MZ and four DZ pairs of twins, each pair consisting of a parkinsonian index case and an asymptomatic co-twin, were collected from the Nationwide Twin Cohort. The control group comprised 14 healthy volunteers. [18F]6-FD PET examinations with a Siemens/CTI 931/08 scanner were performed dynamically over 90 min. The regions-of-interest analysis included the caudate, the putamen and the occipital reference regions. Patlak plots were calculated using occipital tissue input function. The accumulation of [18F]6-FD in the putamen of the asymptomatic co-twins was significantly lower than that in the normal subjects. This result implies that there may be a preclinical stage of Parkinson's disease in the apparently normal co-twins at the time of the PET study.

Impairment of semantic knowledge in Parkinson disease.

BACKGROUND: Parkinson disease (PD) is commonly characterized by cognitive deterioration, but it is still unclear whether PD is associated with semantic impairments. OBJECTIVE: To evaluate semantic knowledge of concepts in patients with idiopathic PD, addressing concrete and abstract concepts, conceptual attributes, and conceptual relations. METHODS: Twelve patients with preserved cognitive status, 12 patients with mildly deteriorated cognitive status, and 12 control subjects were studied. The cognitive status of patients and controls was determined using detailed cognitive testing. Patients were participants in a university-based movement disorder program, and their PD diagnoses were clinically confirmed during long-term follow-up. The 2 patient groups were similar in age, level of education, disease duration, and parkinsonian disability. Patients were required to produce verbal descriptions of concrete and abstract concepts, to give ratings of the importance of concept attributes, and to assess and construct conceptual hierarchies. The description tasks included guiding questions, which were used if the spontaneous productions of the patients lacked any essentials expected in the answers. RESULTS: Patients with mild cognitive deterioration performed less well than the other groups in defining concrete and abstract concepts (P<.001 for both). External guidance did not help them markedly improve their performance. They also had difficulties in tasks calling for knowledge of the importance of given attributes to the concepts and in tasks demanding evaluation of hierarchical semantic relations between concepts (P<.001 for both). CONCLUSION: Semantic disruption is implied in idiopathic PD in association with incipient cognitive impairment.

The quality of life in Parkinson's disease.

The objective of this study was to examine the quality of life in patients with Parkinson's disease (PD) in a community-based sample (n = 228 patients) using a Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) as a measure. Associations to the variables age, age at onset, duration, clinical stage (Hoehn and Yahr), depression (Zung), and dementia (MMSE) were studied. Women scored significantly lower on five of the eight dimensions of SF-36. Depression, as measured in this study, was more common among parkinsonian women than men. Depression was the factor that was associated most significantly with the experienced quality of life, according to SF-36. With physical functioning, only the clinical stage had a more significant association than depression. To improve the quality of life in patients with PD, it is necessary to make every effort to recognize and relieve the depression of patients with PD.

Environmental risk factors in Parkinson's disease.

We studied the environmental risk factors of Parkinson's disease (PD) in Finland, particularly those related to rural environment, in a prevalence material in 1992. The population numbered 196,864 people, including urban and rural areas. In this community-based study, we used a case-control method with personal investigation of the case subjects (n = 123) and matched control subjects (n = 246). Analyses were carried out by conditional logistic regression model. Case subjects had far fewer domestic animals at home during their lifetime, including cows, sheep, pigs, and chickens. The difference was even more obvious in those under the age of 20 years, including also cats and horses, but diminished after 20 years. The number of different animal species was smaller with case subjects as was the duration of animal contacts. Case subjects found their work physically heavier and exercised more. The mean age at onset in ever-smoking men was significantly higher than in never-smoking men. No special reason for non-smoking increased, and a physical reason decreased the risk of PD. Area of birth or living, farming and other occupations, types of drinking water, pesticide and herbicide use, head injuries, use of alcohol, education, and carbon monoxide poisonings were similar among case subjects and control subjects. In conclusion, domestic animals, or something that is connected with the animals, may have a protecting effect against PD. Alternatively, the observed negative associations of domestic animals at home and subsequent PD may only be a marker of other environmental conditions or lifestyles.

[Combination therapy with lisuride and L-dopa in the early stages of Parkinson's disease decreases and delays the development of motor fluctuations. Long-term study over 10 years in comparison with L-dopa monotherapy]. / Kombinationstherapie mit Lisurid und L-Dopa in den Frühstadien der Parkinson-Krankheit verringert und verzögert die Entwicklung motorischer Fluktuationen. Langzeitstudie über 10 Jahre im Vergleich mit einer L-Dopa-Monotherapie.

A randomized, prospective study was carried out in order to investigate the efficacy of a dopamine agonist, lisuride, alone or in combination with levodopa, to minimize or postpone the development of motor fluctuations, compared with levodopa alone during 10 years' treatment of 90 patients with early Parkinson's disease. Only a small, and with time gradually decreasing number of patients obtained enough therapeutic benefit during long-term treatment with lisuride alone. Consequently, levodopa had to be added to the patients' regimen. During combined treatment with lisuride and levodopa the daily dose of levodopa needed for optimal therapeutic response was significantly lower than when using levodopa alone. The addition of levodopa to the lisuride regimen either from the beginning or at any time during long-term treatment according to clinical need, resulted in a therapeutic response in parkinsonian disability equal to that achieved with levodopa alone, but significantly decreased and postponed the development of motor fluctuations, end-of-dose failure and dyskinesias. Severe dopaminergic adverse events leading to withdrawal of the treatment were more frequent during treatment with lisuride and levodopa than with levodopa alone, but the lower mortality rate did not reach the level of statistical significance. In conclusion, according to the results obtained, it seems reasonable to consider a treatment strategy in early Parkinson's disease using a dopamine agonist, like lisuride, as the primary treatment and to delay the addition of levodopa until parkinsonian disability cannot be adequately controlled by a dopamine agonist.

Changing epidemiology of Parkinson's disease in southwestern Finland.

OBJECTIVE: Investigation of the epidemiology of PD in southwestern Finland in 1992 (population 196,864), including urban and rural areas, with a comparison with a similar study, done in the same area in 1971, to evaluate the temporal pattern. METHODS: Community-based method of patient ascertainment with personal investigation of cases. RESULTS: The age-adjusted prevalence (to the Finnish general population in 1991) was 139 per 100,000 population in 1971 and 166 in 1992. Prevalence ratio for PD in men versus women was 1.2 (NS) in 1971 and 1.7 in 1992 (p < 0.001); in the rural versus urban populations the prevalence ratio was 0.8 (NS) in 1971 and 1.3 in 1992 (p = 0.013). The age-specific prevalence rates showed a male preponderance in all age groups in 1992 and a rural preponderance in the age groups over 60 years. In 1992, compared with 1971, the male and rural preponderance occurred in the age groups over 70 years. The age-adjusted incidence was 15.7 per 100,000 population in 1971 and 14.9 in 1992. Relative risk for PD in men versus women was 0.9 (NS) in 1971 and 1.9 (p < 0.001) in 1992, and in rural versus urban populations 1.4 (p = 0.093) in 1992. CONCLUSIONS: A very significant male and a significant rural predominance, not seen in 1971, suggests a possible environmental causative factor, perhaps more frequent in the rural environment, associated with PD. Men may be either more exposed to it or more susceptible to its effects than women.

COMT inhibition in the treatment of Parkinson's disease.

A new approach in the treatment of Parkinson's disease is the inhibition of catechol-O-methyltransferase (COMT) with new generation COMT inhibitors, entacapone and tolcapone. Entacapone acts mainly peripherally whereas tolcapone acts both peripherally and centrally. They induce a dose-dependent inhibition of COMT activity in erythrocytes and a significant decrease in the plasma levels of 3-O-methyldopa, indicating their effectiveness as COMT inhibitors. Consequently, they increase the elimination half-life of levodopa and thus prolong the availability of levodopa to the brain without significantly affecting the Cmax or tmax of levodopa. Clinically, the improved levodopa availability is seen as prolonged motor response to levodopa/DDC inhibitor and also as prolonged duration of dyskinesias in Parkinson's disease patients with end-of-dose fluctuations. The dyskinesias are managed by decreasing the daily levodopa dose in Parkinson's disease patients with end-of-dose fluctuations. Both pharmacokinetically and clinically the 200-mg dose of entacapone is the most effective dose compared with placebo. For tolcapone 100 and 200 mg have most often proved to be the optimal doses. Based on the duration of COMT inhibition entacapone is administered with each levodopa/DDC inhibitor dose whereas tolcapone is given three times daily. Both entacapone and tolcapone are well-tolerated. However, there seems to be a trend for tolcapone to induce more often diarrhoea and increase in liver transaminases compared with entacapone. Thus, COMT inhibitors are clinically significant and beneficial adjunct to levodopa therapy in Parkinson's disease patients with end-of-dose fluctuations. Their effects and significance also in the treatment of de novo patients need to be clarified.

Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group.

OBJECTIVE: To study the effect and safety of entacapone as an adjunct to levodopa treatment in patients with PD with wearing-off motor fluctuations. BACKGROUND: Entacapone is a catechol-O-methyltransferase (COMT) inhibitor that has been shown to increase the area under the concentration-time curve of plasma levodopa by decreasing its systemic elimination, thereby promoting and improving therapeutic response to it. METHODS: A total of 171 parkinsonian patients with wearing-off-type motor fluctuations participated in a 6-month randomized, placebo-controlled, double-blind, parallel-group study. The extent of therapeutic response was elicited in the first hand with home diary recordings of "on" and "off" times by the patient and with Unified Parkinson's Disease Rating Scale scoring by the examiner. The patients took either 200 mg entacapone or identical placebos concomitantly with each daily levodopa dose (four to 10 times a day). RESULTS: Patients' home diaries indicated that entacapone increased the mean (+/- SD) "on" time significantly (9.3 +/- 2.2 to 10.7 +/- 2.2 hours; p < 0.01) and correspondingly decreased the "off" time significantly (5.3 +/- 2.2 to 4.2 +/- 2.2 hours; p < 0.001). The average benefit derived from a daily levodopa dose as related by the patients was increased significantly (p < 0.01). The daily levodopa dose was reduced significantly in the entacapone group, the difference between the groups being 102 mg (p < 0.01). The entacapone-derived increase in the benefit from levodopa was lost almost completely following its withdrawal. Entacapone was well tolerated. Dopaminergic adverse events, which increased, were ameliorated by reducing the levodopa dose. Diarrhea was the most common nondopaminergic adverse event. CONCLUSIONS: Long-term entacapone treatment effectively prolonged the beneficial response to levodopa in parkinsonian patients with the wearing-off phenomenon. The improvement occurred irrespective of the reduction of the levodopa dose.

Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis.

INTRODUCTION: The Parkinson's Disease Research Group of the United Kingdom (PDRG-UK) reported increased mortality in PD patients treated with levodopa plus selegiline compared with those treated with levodopa alone. METHODS: We performed a meta-analysis on five long-term, prospective, randomized trials of selegiline in patients with untreated PD. Included in the analysis were four randomized, double-blind, placebo-controlled studies and one randomized, double-blind, placebo-controlled study of 2 years' duration followed by long-term, open follow-up. RESULTS: The mean duration of follow-up was 4.1 +/- 1.8 years. There were 14 deaths in 297 selegiline-treated patients (4.7%) and 17 deaths in 292 non-selegiline-treated patients (5.8%). The hazard ratio for mortality was 1.02 (95% CI 0.44 to 2.37; p = 0.96). An analysis restricted to patients receiving only levodopa with or without selegiline noted 11 deaths in 257 levodopa/selegiline-treated patients (4.3%) and 11 deaths in 254 patients treated with levodopa alone (4.3%). The hazard ratio was 1.06 (95% CI 0.44 to 2.55; p = 0.90). Death rate per 1,000 patient years was 11.4 in the selegiline group and 14.2 in the nonselegiline group. Kaplan-Meier survival curves reflecting pooled survival data showed no significant difference in duration of survival. The hazard ratio was 0.84 (95% CI 0.41 to 1.70; p = 0.63) for selegiline- versus non-selegiline-treated patients and 1.05 (95% CI 0.46 to 2.43; p = 0.91) for selegiline/levodopa- versus levodopa-treated patients. CONCLUSION: These results contrast with those of the PDRG-UK study and demonstrate no increase in mortality associated with selegiline treatment whether or not patients also received levodopa.

Population pharmacodynamic modeling of levodopa in patients with Parkinson's disease receiving entacapone.

OBJECTIVE: To assess the pharmacodynamics of levodopa among patients with Parkinson's disease showing end-of-dose fluctuations at different doses of entacapone. METHODS: Nineteen patients participated in a randomized, double-blind phase II study with a crossover design. Doses of 50, 100, 200, or 400 mg entacapone or placebo were given with the patient's individual levodopa-dopa decarboxylase inhibitor dose. Blood samples were withdrawn for pharmacokinetic analysis, and the clinical response was measured using the motor part of the Unified Parkinson's Disease Rating Scale. A population pharmacodynamic model was developed with the NONMEM program. RESULTS: A sigmoidal Emax model with an effect compartment was used to relate plasma concentrations of levodopa with clinical response. In the population analysis two covariate relationships were found. The first was E0 = 55.2, [1 + 0.012. (Dur-13)], where E0 is the initial motor Unified Parkinson's Disease Rating Scale score, and Dur is the duration of disease in years. The second was C50(carbidopa) = 951 ng/ml; C50(benserazide) = 1238 ng/ml, where C50 is the steady-state plasma concentration of levodopa eliciting half of maximum attainable effect, and carbidopa and benserazide are the dopa decarboxylase inhibitors given in the study. No effect of entacapone on clinical response beyond its influence on levodopa pharmacokinetics was found. Interindividual and interoccasion variabilities were estimated. CONCLUSIONS: A population pharmacodynamic model for levodopa was built that took into account interindividual and intraindividual variability. The main finding was that entacapone does not alter the concentration-effect curve of levodopa, suggesting that entacapone acts at the level of peripheral pharmacokinetics of levodopa and that plasma levels of 3-O-methyldopa have a negligible role in the pharmacodynamics of levodopa.

Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group.

This multicentre randomised double-blind 3- to 5-year trial was designed to assess whether initial therapy with cabergoline alone or in combination with levodopa prevents or delays the occurrence of long term motor complications in patients with early Parkinson's disease. Patients eligible for study inclusion (n = 412) had early idiopathic Parkinson's disease (Hoehn and Yahr stages 1 to 3) and had received no previous treatment with levodopa, selegiline or dopamine agonists. Patients were randomised to receive either cabergoline (0.25 to 4 mg once daily) or levodopa (100 to 600 mg/day) titrated over a maximum period of 24 weeks. Once the optimum or maximum tolerated dose was achieved, it was maintained up to the end-point (development of motor complications confirmed at 2 consecutive 3-month visits) or up to a minimum of 3 years' treatment. Open labelled levodopa was added in both treatment arms when the improvement in motor disability [Unified Parkinson's Disease Rating Scale (UPDRS) factor III] decreased below 30% vs baseline. Both treatments improved motor disability, decreasing UPDRS factor III scores and factor II scores for activities of daily living. The development of motor complications (end-point) was significantly less frequent in patients treated with cabergoline than in levodopa recipients (22% vs 34%; p < 0.02). The relative risk of developing motor complications during treatment with cabergoline was more than 50% lower than with levodopa. Serious adverse events, either drug related or not, were slightly more frequent in cabergoline-treated patients (31%) than in those treated with levodopa (25%). The withdrawal rate in the cabergoline vs levodopa group was 16 vs 13%. In conclusion, the study shows that, in patients with early Parkinson's disease, cabergoline is effective either as monotherapy or combined with levodopa. Moreover, starting treatment with cabergoline significantly delays the development of motor complications.

Correlation between neuromorphometry in the substantia nigra and clinical features in Parkinson's disease using disector counts.

Previous studies based on single sections have suggested a significant correlation between pigmented neuronal loss in the substantia nigra (SN) and clinical features in Parkinson's disease (PD). However, disector (DS) counts-unbiased and accurate stereological estimates have not been available. To evaluate total neuron numbers in the pars compacta of the substantia nigra (SNpc) in relation to clinical features, we estimated the neuron counts in the SNpc by the DS method in brain samples from 12 controls and 12 PD patients. The total number of pigmented neurons in the whole SNpc was significantly reduced in PD patients (to 45% of the control mean, P < 0.001). The density of pigmented neurons (neuron/mm3) was reduced to 51% of the average control value (P < 0.001). No significant difference was seen in the volume (mm3) of the SNpc between PD patients and controls. Furthermore, the total number of pigmented neurons in the SNpc showed a significant negative correlation with the duration of disease (r = -0.86, P < 0.001) and with the stage of disease (r = -0.58, P < 0.05) in PD patients. Using an unbiased neuron counting method, these relationships, for the first time, demonstrate that the more severe pigmented neuronal loss in the SNpc is associated with the longer duration and the more severe stage of disease in PD patients.

Cabergoline in the treatment of early Parkinson's disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. The PKDS009 Collaborative Study Group.

Cabergoline is a potent D2 receptor agonist with a half-life of 65 hours that may provide continuous dopaminergic stimulation administered once daily. In this study, we randomized de novo Parkinson's disease (PD) patients to treatment with increasing doses of cabergoline (0.25 to 4 mg/d) or levodopa (100 to 600 mg/d) up to the optimal or maximum tolerated dose. Decreases of > 30% in motor disability (Unified Parkinson's Disease Rating Scale Factor III) versus baseline were considered indicative of clinical improvement. If 30% improvement was not achieved, levodopa/ carbidopa could be added on an open basis. Of the 208 patients entered in the cabergoline group, 175 remained in the study for 1 year at a mean dose of 2.8 mg/d; in the levodopa group, 176 of the 205 patients entered were still on study after 1 year at a mean dose of 468 mg/d. The proportion of patients requiring additional levodopa/carbidopa increased in the cabergoline group from 18% at 6 months to 38% at 1 year versus 10% (p = 0.05) at 6 months and 18% (p < 0.01) at 1 year in the levodopa group. The proportion of patients showing clinical improvement did not differ significantly between the two groups, or between the subgroups on monotherapy, at any endpoint. Irrespective of levodopa/carbidopa addition, 81% of patients in the cabergoline group and 87% of patients in the levodopa group were clinically improved at 1 year (p = 0.189); the corresponding figures for the subgroup on monotherapy were 79% in the cabergoline-treated patients and 86% in the levodopa-treated patients (p = 0.199). The mean difference versus baseline in Unified Parkinson's Disease Rating Scale Factor III scores in patients who remained on monotherapy up to 1 year was 12.6 (95% confidence interval [CI]: 10.8, 14.3) in the cabergoline group and 16.4 (95% CI: 14.8, 18.0) in the levodopa group. Adverse events occurred in 76% of patients on cabergoline and in 66% of patients on levodopa. The severity profile for reported events was similar for the two agents. The results of this study indicate that cabergoline treatment for up to 1 year is only marginally less effective than levodopa in the proportion of patients who can be treated in monotherapy. More than 60% of de novo PD patients could be managed on cabergoline alone up to 1 year. In the patients in whom levodopa/carbidopa was needed, the combination therapy provided efficacy similar to that obtained with levodopa alone, with a relevant sparing of levodopa.

Striatal 6-[18F]fluorodopa accumulation after combined inhibition of peripheral catechol-O-methyltransferase and monoamine oxidase type B: differing response in relation to presynaptic dopaminergic dysfunction.

The aim was to investigate the effects of inhibition of monoamine oxidase type B (MAO-B) with selegiline alone and the combined inhibition of peripheral catechol-O-methyltransferase (COMT) with entacapone and MAO-B with selegiline on striatal 6-[18F]fluorodopa (FDOPA) accumulation, and whether the effect of entacapone + selegiline on FDOPA uptake differed depending on the severity of the presynaptic dopaminergic dysfunction. Thus, eight healthy controls, eight de novo patients with Parkinson's disease (PD), and 18 levodopa-treated PD patients were investigated with positron emission tomography (PET). Half of the subjects in each population belonged to the selegiline group and half to the entacapone + selegiline group. Both groups were studied twice with PET using FDOPA. After the first (baseline) FDOPA PET investigation, both groups were on 2 weeks of selegiline treatment, 10 mg daily. Thereafter, the second FDOPA PET was performed for all subjects with a premedication administered 60 min before the PET imaging; one group received 10 mg of selegiline, and the other group received a single 400 mg dose of entacapone coadministered with 10 mg of selegiline. Selegiline treatment alone had no significant influence on striatal FDOPA metabolism. The FDOPA accumulation, expressed as striatal-to-occipital ratios and modified decarboxylation coefficients (k3R0), increased significantly after entacapone + selegiline administration in all subject populations. The FDOPA uptake rate constant (Ki) remained virtually unchanged in controls and in de novo patients but decreased significantly in levodopa-treated PD patients after entacapone + selegiline intake. Entacapone + selegiline administration did not influence significantly the unidirectional blood-to-brain clearance for FDOPA (K1D) or the relative dopadecarboxylase activity (k3D). The changes in the studied parameters after entacapone + selegiline administration probably reflect the effects of entacapone, since entacapone alone has caused similar changes in previous PET studies. Response in FDOPA accumulation to entacapone + selegiline was higher in controls and de novo patients compared with levodopa-treated PD patients. The milder response in levodopa-treated patients might reflect the reduced ability of the degenerated dopaminergic neurons to utilize the prolonged FDOPA availability, produced by entacapone.

A quantitative morphometrical study of neuron degeneration in the substantia nigra in Parkinson's disease.

We studied the pigmented neurons of the substantia nigra (SN) from 8 controls and 20 patients with Parkinson's disease (PD) using a computerized morphometric methodology. On the basis of neuronal topography, several anatomic regions were outlined in the SN. In these subregions the area, perimeter, diameter of the cell bodies and cell numbers were measured and were counted in the controls and PD patients. The measurements were made at the level of the exit of the third cranial nerve from the brain stem. In PD patients, when the whole SN was considered, the mean area, mean perimeter and diameter of the pigmented cell bodies were significantly reduced by 35%, 20% and 21% respectively from the control mean values. Regionally, the pigmented neuron area in the medial ventral part (VM), medial dorsal part (DM), lateral ventral part (VL), lateral dorsal part (DL) and pars lateralis part (PL) showed a significant reduction of 33-41% as compared to controls. In these subregions, a significant decrease in PD patients from the control mean values was seen both in the pigmented neuron perimeter, by 19-26%, and the diameter by 19-25%. This decrease in cell size suggests that, in PD patients, the remaining pigmented neurons in the SN are in a process of degeneration and atrophy. In PD patients the number of pigmented neurons in the whole SN decreased about 76% from control values. Evaluation of the influence of cell size on the apparent quantity of cells in sections indicates, however, that in PD patients the impact of true loss of pigmented neurons is far more dramatic than the impact of their decrease in size.

A double-blind pharmacokinetic and clinical dose-response study of entacapone as an adjuvant to levodopa therapy in advanced Parkinson's disease.

A dose-response study of the effects of entacapone on the pharmacokinetics and metabolism of levodopa and on the clinical response to levodopa was carried out in 20 parkinsonian patients with levodopa-related fluctuations. A randomized, double-blind, single-graded-dose, crossover design of five 1-day treatment periods each 1 week apart was used. Entacapone (50, 100, 200, or 400 mg) or placebo was given at 8 a.m. with the patient's individual dose of levodopa/dopa decarboxylase inhibitor. The inhibition of soluble catechol-O-methyltransferase (S-COMT) in red blood cells (RBCs) and plasma concentrations of levodopa, its metabolites, and entacapone were measured and motor responses were quantified at 30min intervals using the motor part of the Unified Parkinson's Disease Rating Scale. Entacapone brought about a dose-dependent decrease in S-COMT activity in the RBCs, maximally by 48% at 400 mg. With a 200-mg dose of entacapone, the area under the plasma concentration-time curve (AUC) and half-life of levodopa increased (p < 0.001); the AUCs of 3-O-methyldopa and homovanillic acid decreased (p = 0.01 and p < 0.001, respectively) and that of 3,4-dihydroxyphenylacetic acid increased (p < 0.001). Entacapone prolonged the duration of the motor response to levodopa by 33 min (p = 0.04) and dyskinesias by 45 min (p = 0.003) without affecting their magnitude; the highest increase in duration of these responses occurred with 200 mg of entacapone. Thus, on pharmacokinetic and clinical grounds, the 200-mg dose of entacapone was the most effective. Dose-related responses to entacapone demonstrated its value in the treatment of parkinsonian patients with levodopa-related fluctuations by prolonging the antiparkinsonian response to the levodopa dose.