Comparisons of therapeutic effects of levodopa,levodopa and selegiline,and bromocriptine in patients with early,mild Parkinson's disease: three year interim report. Parkinson's Disease Research Group in the United Kingdom.

OBJECTIVE--To determine the optimum treatment for early Parkinson''s disease. DESIGN--An open, long term, prospective randomised trial conducted by the Parkinson''s Disease Research Group of the United Kingdom. SETTING--93 hospitals throughout the United Kingdom. SUBJECTS--782 patients with early Parkinson''s disease who were not receiving dopaminergic treatment. INTERVENTIONS--Patients allocated to treatment with levodopa/dopa decarboxylase inhibitor alone (arm 1), levodopa/decarboxylase inhibitor/selegiline in combination (arm 2), or bromocriptine (arm 3). MAIN OUTCOME MEASURES--Disability assessment as judged by improvement on Hoehn and Yahr, modified Webster, and North Western University disability scales. Adverse event profile and mortality ratios. RESULTS--Interim results indicate that all three treatment regimens led to improvement in baseline disabilities after 12 months'' treatment and that deterioration in control was apparent by three years. No significant differences were found between the results of treatment in arm 1 and arm 2, but both were significantly more effective than bromocriptine (arm 3) and had fewer early adverse reactions. The adjusted difference (95% confidence interval) in Webster rating for arm 3 v 1 was 0.93 points (0.27 to 1.50; p = 0.0058) and for arm 3 v 2 was 1.25 points (0.61 to 1.89; p = 0.0002). The incidence of dyskinesias and motor oscillations, however, was significantly lower in arm 3 (2% and 5%, respectively) than in arm 1 (27% and 33%, respectively) and arm 2 (34% and 35%, respectively). CONCLUSIONS--As there were no marked differences in functional improvement between the three groups the choice of treatment in the early stages of Parkinson''s disease may not be critical.     

Drug treatment of Parkinson's disease.

A wide variety of drugs is available for treating Parkinson''s disease, including anticholinergics, amantadine levodopa, dopamine agonists, and selegiline. In younger patients (less than 50) levodopa is usually delayed provided that adequate relief of symptoms can be achieved with other drugs. In older patients (greater than 70) levodopa should be started as soon as symptom relief is required. Between these ages there is no consensus, but at present most such patients should probably be given controlled release levodopa before a dopamine agonist is added. Fluctuations can often be alleviated by giving controlled release preparations of levodopa, by giving small doses at frequent intervals, by adding selegiline or a long acting oral agonist, or by subcutaneous apomorphine. Dyskinesia can be peak dose, diphasic, or "off period." The diphasic form is hardest to alleviate. Psychiatric side effects should initially be managed by changing the antiparkinsonian treatment before resorting to antipsychotic drugs.     

Parkinson's disease.

In Parkinson''s disease there is degeneration of neurons in the substantia nigra, with consequent depletion of the neurotransmitter dopamine. The triad of tremor, rigidity and bradykinesia is the clinical hallmark. Drugs currently used for palliative therapy fall into three categories: anticholinergic agents, dopamine precursors (levodopa combined with extracerebral decarboxylase inhibitors) and artificial dopamine agonists. It has been argued, on theoretical grounds, that some drugs slow the progress of Parkinson''s disease, although no firm evidence has supported this. Treatment must be individualized, and more than one type of drug can be given concurrently after a careful build-up in dosage. We review the adverse effects of various drugs and consider new developments such as slow-release preparations, selective D-1 and D-2 agonists and transplants of dopaminergic cells into the brain. The treatment of Parkinson''s disease can be demanding, rewarding and sometimes frustrating, but it remains a most challenging exercise in pharmacotherapy.     

Effects of levodopa therapy in Parkinson's disease II. Measurement of behavioural changes

Forty-seven patients with Parkinson''s disease were evaluated prior to and during levodopa treatment (at five weeks and at six months), to obtain quantitative measures of the effects of the disease and of levodopa on a variety of cognitive and psychomotor functions, by means of psychological tests and special apparatus. Analysis of the findings in relation to a comparable control group shows that before treatment patients had impaired performance of all motor tasks, but no differences in cognitive functioning were found. Most motor functions had improved after five weeks on levodopa and this improvement was maintained at the six-month follow-up, but cognitive functions remained largely unchanged. The relationship between patients'' age, disability, duration of illness and drug tolerance is also discussed in relation to the functions measured.     

Treatment of Parkinson's disease.

Pharmacotherapy with levodopa for Parkinson''s disease provides symptomatic benefit, but fluctuations in (or loss of) response may eventually occur. Dopamine agonists are also helpful and, when taken with low doses of levodopa, often provide sustained benefit with fewer side effects; novel agonists and new methods for their administration are therefore under study. Other therapeutic strategies are being explored, including the use of type B monoamine oxidase inhibitors to reduce the metabolic breakdown of dopamine, catechol-O-methyltransferase inhibitors to retard the breakdown of levodopa, norepinephrine precursors to compensate for deficiency of this neurotransmitter, glutamate antagonists to counteract the effects of the subthalamic nucleus, and various neurotrophic factors to influence dopaminergic nigrostriatal cells. Surgical procedures involving pallidotomy are sometimes helpful. Those involving cerebral transplantation of adrenal medullary or fetal mesencephalic tissue have yielded mixed results; benefits may relate to the presence of growth factors in the transplanted tissue. The transplantation of genetically engineered cell lines will probably become the optimal transplantation procedure. The cause of Parkinson''s disease may relate to oxidant stress and the generation of free radicals. It is not clear whether treatment with selegiline hydrochloride (a type B monoamine oxidase inhibitor) delays the progression of Parkinson''s disease, because the drug also exerts a mild symptomatic effect. Daily treatment with vitamin E (a scavenger of free radicals) does not influence disease progression, perhaps because of limited penetration into the brain.     

One to Two Year Treatment of Parkinson's Disease with Levodopa

One hundred patients with Parkinson''s disease were treated with levodopa for more than a year at UCLA Medical Center. They were examined at given intervals and their improvement was graded. The optimum therapeutic dose was attained by balancing side effects against relief of symptoms and ranged from 1.5 grams to 8.0 grams per day (average 4.3 grams). There is no doubt that levodopa is the most effective treatment now available for Parkinson''s disease. At the end of the first year, 60 percent of the patients improved 50 percent or better, and 10 percent were considered symptom-free. All major symptoms of this disease, including rigidity, akinesia and tremor, improved in variable degree.There were no serious abnormalities in the routine clinical laboratory tests. The comon side effects included nausea, vomiting and choreoathetoid dyskinesias. The side effects were not life threatening, but occasionally were major therapeutic challenges.Maximal benefits with minimal side effects were achieved only by careful adjustments of the levodopa dosage as the months went by. This needed careful management by the physician and cooperation by the patient. Anticholinergic medications or amantadine hydrochloride, sometimes both, usually supplemented the effect of the levodopa.     

The effects of levodopa therapy in patients with Parkinson's disease I. Clinical response

Eighty-eight patients with Parkinson''s disease were treated with levodopa. A group of elderly patients 65 years and older was compared with a second group under the age of 65, and it was found that generally the younger patients could be treated with greater success than the older ones. Most of the elderly could not tolerate the large doses required to produce optimal physical recovery. Severity of complications forced discontinuance of treatment in a larger percentage of elderly patients. The rate of complications was about equal in the two groups, except the incidence of confusion, which was significantly higher in the elderly. Of the two deaths that occurred, both were in the older group. Results of treatment were better in patients whose families gave positive support.     

Markers of Disease Severity Are Associated with Malnutrition in Parkinson's Disease

Objective

In Parkinson''s disease (PD), commonly reported risk factors for malnutrition in other populations commonly occur. Few studies have explored which of these factors are of particular importance in malnutrition in PD. The aim was to identify the determinants of nutritional status in people with Parkinson''s disease (PWP).

Methods

Community-dwelling PWP (>18 years) were recruited (n = 125; 73M/52F; Mdn 70 years). Self-report assessments included Beck''s Depression Inventory (BDI), Spielberger Trait Anxiety Inventory (STAI), Scales for Outcomes in Parkinson''s disease – Autonomic (SCOPA-AUT), Modified Constipation Assessment Scale (MCAS) and Freezing of Gait Questionnaire (FOG-Q). Information about age, PD duration, medications, co-morbid conditions and living situation was obtained. Addenbrooke''s Cognitive Examination (ACE-R), Unified Parkinson''s Disease Rating Scale (UPDRS) II and UPDRS III were performed. Nutritional status was assessed using the Subjective Global Assessment (SGA) as part of the scored Patient-Generated Subjective Global Assessment (PG-SGA).

Results

Nineteen (15%) were malnourished (SGA-B). Median PG-SGA score was 3. More of the malnourished were elderly (84% vs. 71%) and had more severe disease (H&Y: 21% vs. 5%). UPDRS II and UPDRS III scores and levodopa equivalent daily dose (LEDD)/body weight(mg/kg) were significantly higher in the malnourished (Mdn 18 vs. 15; 20 vs. 15; 10.1 vs. 7.6 respectively). Regression analyses revealed older age at diagnosis, higher LEDD/body weight (mg/kg), greater UPDRS III score, lower STAI score and higher BDI score as significant predictors of malnutrition (SGA-B). Living alone and higher BDI and UPDRS III scores were significant predictors of a higher log-adjusted PG-SGA score.

Conclusions

In this sample of PWP, the rate of malnutrition was higher than that previously reported in the general community. Nutrition screening should occur regularly in those with more severe disease and depression. Community support should be provided to PWP living alone. Dopaminergic medication should be reviewed with body weight changes.     

Levodopa combined with peripheral decarboxylase inhibition in Parkinson's disease

The authors report their experience, over a 26-month period, in the management of 60 parkinsonian patients with the combination of levodopa and an inhibitor of peripheral dopa-decarboxylase, Ro 4-4602. This approach to Parkinson''s disease is useful, safe, and at least as effective as levodopa alone. To date there have been no recognizable toxic effects attributable to Ro 4-4602. This agent appears to prolong the duration of action of levodopa, smoothing out its therapeutic effects. The percentage of patients obtaining a very good and excellent response is slightly increased. There is a possible diminution in the late-occurring bradykinetic and hypotonic freezing episodes. Nausea and cardiac arrhythmias are lessened, as are the incidence and severity of hypotension. Abnormal involuntary movements remain the limiting adverse side effect.     

A community survey of Parkinson's disease.

In a rural community of 80,000 people 69 patients were identified as having a diagnosis of Parkinson''s disease. After interview and examination we found that 55 met the generally accepted diagnostic criteria for Parkinson''s disease, 4 had possible Parkinson''s disease, 6 had essential tremor, 2 had dementia and 2 had other conditions. The patients with Parkinson''s disease had clinical and epidemiologic characteristics similar to those of patients in previous, mainly hospital-based, studies. These characteristics included mean age at onset (63 years), frequency rate of dementia (20%) and presence of postural tremor (11%). The pattern of treatment varied, some patients receiving more medication than is usual for the severity of their illness, and some patients receiving less than is usual. Parkinson''s disease can be difficult to diagnose and manage because of the clinical variation between patients in presentation and response to treatment.     

Gender differences in Parkinson's disease

Because estrogen has numerous effects on dopamine neurotransmission, many researchers are interested in its possible use to either slow the progression or reduce the risk of Parkinson's disease (PD). The incidence of PD is greater in men than in women. Gender differences in neurotoxicity have been observed, and basic research in experimental animals indicates that estrogen protects neurons from various forms of injury. However, the results of retrospective surveys of the neuroprotective effects of estrogen replacement in PD have been mixed, with some showing no effect on risk and others showing a reduction in risk. A mildly significant gender difference in disability and quality-of-life reporting has been noted, with women citing greater disability and reduced quality of life. Gender differences have been shown in response to treatment of PD, for example, in how levodopa is metabolized-women have greater levodopa bioavailability. In the Parkinson's Disease on Estrogen Therapy Replacement in the Menopause Years (POETRY) study, participants were found to have improved scores on the Unified Parkinson Disease Rating Scale. Based on the POETRY results, it is hypothesized that estrogen replacement therapy (ERT) may lead to improvement in PD symptoms and provide an opportunity to reduce the dosage of antiparkinsonian medication in women.     

左旋多巴/ 卡比多巴联合恩他卡朋治疗帕金森病的临床研究

目的:观察左旋多巴/卡比多巴联合恩他卡朋(levodopa/carbidopa combined with entacapone,LC+E)治疗帕金森病(Parkinson's disease,PD)的临床效果。方法:选择我院2013年1月~2014年6月收治的112例PD患者,随机分为两组。其中对照组52例采用左旋多巴/卡比多巴(LC)治疗,观察组60例采用左旋多巴/卡比多巴联合恩他卡朋(LC+E)治疗。观察并比较两组治疗前后帕金森病评分量表(Unified Parkinson's Disease Rating Scale,UPDRS)的评分变化情况。结果:与治疗前比较,治疗后两组UPDRS-II日常生活能力评分,UPDRS-III运动能力评分显著下降,而UPDRS-VI SCHWABENGLAND日常活动能力评分显著上升,差异有统计学意义(P0.05);观察组各项变化情况比对照组明显,差异有统计学意义(P0.05)。两组UPDRS-I精神、行为、情绪和Hoehn与Yahr分级均无显著改善,差异无统计学意义(P0.05)。结论:左旋多巴/卡比多巴联合恩他卡朋可明显缓解PD症状,疗效优于左旋多巴/卡比多巴治疗,且安全性高,值得临床推广。     

Comparison of endothelial progenitor cells in Parkinson's disease patients treated with levodopa and levodopa/COMT inhibitor

Background

Levodopa treatment in Parkinson''s disease (PD) increases in serum homocysteine levels due to its metabolism via catechol O-methyltransferase. Endothelial progenitor cells (EPCs) have the capacity to differentiate into mature endothelial cells and are markers for endothelial functions and cardiovascular risks. Along with traditional vascular risk factors, hyperhomocysteinemia is known to decrease the level of EPCs. In the present study, we hypothesized that that levodopa-induced hyperhomocysteinemia leads to a change in EPC levels.

Methodology/Principal Findings

We prospectively enrolled PD patients who had been prescribed either levodopa/carbidopa (PD-L group, n = 28) or levodopa/carbidopa/COMT inhibitor (PD-LC group, n = 25) for more than 1 year. The number of circulating EPCs was measured by flow cytometry using dual staining of anti-CD34 and anti-KDR antibodies. The EPCs were divided into tertiles based on their distributions and a logistic regression analysis was used to estimate independent predictors of the highest tertile of EPCs. The number of endothelial progenitor cells was significantly decreased in PD-L patients (118±99/mL) compared with either PD-LC patients (269±258/mL, p = 0.007) or controls (206±204/mL, p = 0.012). The level of homocysteine was significantly increased in PD-L patients (14.9±5.3 µmol/L) compared with either PD-LC patients (11.9±3.0 µmol/L, p = 0.028) or controls (11.1±2.5 µmol/L, p = 0.012). The level of homocysteine was negatively correlated with endothelial progenitor cell levels (r = −0.252, p = 0.028) and was an independent predictor of the highest tertile of endothelial progenitor cell levels (OR; 0.749 [95% CI: 0.584–0.961]).

Conclusions/Significance

These data indicate that a higher consumption of EPC for restoration of endothelial damage may be associated with chronic levodopa treatment in PD patients.     

Multiple Modes of Impulsivity in Parkinson's Disease

Cognitive problems are a major factor determining quality of life of patients with Parkinson''s disease. These include deficits in inhibitory control, ranging from subclinical alterations in decision-making to severe impulse control disorders. Based on preclinical studies, we proposed that Parkinson''s disease does not cause a unified disorder of inhibitory control, but rather a set of impulsivity factors with distinct psychological profiles, anatomy and pharmacology. We assessed a broad set of measures of the cognitive, behavioural and temperamental/trait aspects of impulsivity. Sixty adults, including 30 idiopathic Parkinson''s disease patients (Hoehn and Yahr stage I–III) and 30 healthy controls, completed a neuropsychological battery, objective behavioural measures and self-report questionnaires. Univariate analyses of variance confirmed group differences in nine out of eleven metrics. We then used factor analysis (principal components method) to identify the structure of impulsivity in Parkinson''s disease. Four principal factors were identified, consistent with four different mechanisms of impulsivity, explaining 60% of variance. The factors were related to (1) tests of response conflict, interference and self assessment of impulsive behaviours on the Barrett Impulsivity Scale, (2) tests of motor inhibitory control, and the self-report behavioural approach system, (3) time estimation and delay aversion, and (4) reflection in hypothetical scenarios including temporal discounting. The different test profiles of these four factors were consistent with human and comparative studies of the pharmacology and functional anatomy of impulsivity. Relationships between each factor and clinical and demographic features were examined by regression against factor loadings. Levodopa dose equivalent was associated only with factors (2) and (3). The results confirm that impulsivity is common in Parkinson''s disease, even in the absence of impulse control disorders, and that it is not a unitary phenomenon. A better understanding of the structure of impulsivity in Parkinson''s disease will support more evidence-based and effective strategies to treat impulsivity.     

Effect of new dopamine-blocking agent (oxiperomide) on drug-induced dyskinesias in Parkinson's disease and spontaneous dyskinesias.

Oxiperomide, a new dopamine-receptor antagonist, was found to decrease dyskinesias in patients with Parkinson''s disease receiving levodopa or other dopamine agonists without necessarily increasing Parkinsonian symptoms. Oxiperomide also decreased spontaneous dyskinesias in those with tics and chorea and to a less extent in those with torsion dystonia, without necessarily causing Parkinsonism. These results provide evidence that more than one population of dopamine receptors exist in the extra pyramidal system, and encourage the search for selective dopamine antagonists.     

帕金森病伴抑郁患者DBS 术后帕罗西汀治疗疗效观察

目的:研究丘脑底核(STN)脑深部电刺激(DBS)治疗帕金森病(PD)合并抑郁障碍术后服用帕罗西汀治疗的疗效。方法:将38例合并抑郁障碍的PD患者随机分为三组,行丘脑底核脑深部电极植入术,术后空白对照组不服用任何抗抑郁药物,药物治疗组服用帕罗西汀每日一次,每次20mg,安慰剂组服用安慰剂。术前一周,术后1个月、2个月和3个月进行随访和临床评价。结果:抑郁患者术后抑郁障碍症状如焦虑、绝望和激越症状也有不同程度好转,应用安慰剂后,患者术后抑郁障碍程度好转程度大于空白对照组(P<0.05),而应用帕罗西汀后术后3个月汉密尔顿抑郁量表评分(HAMD)下降程度显著低于空白对照组及安慰剂组(P<0.05)。结论:表明STN-DBS术后PD患者的抑郁症状有所改善,辅助抗抑郁药物治疗效果更佳。     

美多芭联合息宁对帕金森病患者症状波动 及便秘的影响

目的评价美多芭联合息宁分服对帕金森病患者症状波动和便秘的影响。方法选取我院帕金森病患者104例,随机分为分服组与对照组各52例。分服组患者采用美多芭联合息宁治疗,对照组患者单纯采用美多芭治疗。在患者入组时、治疗第4周和治疗第8周时分别比较两组患者日记记录的"开"和"关"时间以及帕金森病统一评分量表Ⅲ(UPDRS-Ⅲ)、PAC-SYM评分和PDQ-39评分结果。结果治疗后两组患者均延长了"开"时间,缩短"关"时间。分服组在治疗第4周和第8周时延长"开"时间、缩短"关"时间情况优于对照组,差异均有统计学意义(均P0.05)。治疗后两组患者UPDRS-Ⅲ评分均有所改善。治疗第4周时分服组患者UPDRS-Ⅲ评分、PAC-SYM评分与对照组比较差异无统计学意义(均P0.05);治疗第8周时分服组患者UPDRS-Ⅲ和PAC-SYM评分均低于对照组,差异有统计学意义(均P0.05)。两组患者治疗后PDQ-39评分均降低,治疗第4周时分服组患者PDQ-39评分与对照组相比差异无统计学意义(P0.05);治疗第8周时分服组患者PDQ-39评分低于对照组,差异有统计学意义(P0.05)。结论美多芭联合息宁分服对帕金森病患者症状波动和便秘的改善均优于单用美多芭治疗,能提高患者生活质量,值得临床推广。     

Case control polysomnographic studies of sleep disorders in Parkinson's disease

Background

The relationship between a number of primary sleep disorders and Parkinson''s disease (PD) is still debated. There are limited case control polysomnographic studies in PD and most of these study sample sizes are small.

Methodology/Findings

We conducted one of the largest case-control studies involving overnight polysomnographic evaluation, with prospective recruitment of unselected Parkinson''s disease patients and healthy controls from an Asian population. The cases were recruited from the specialized movement disorder outpatient clinics in a tertiary referral center, and controls from the same geographical locations. All subjects underwent an overnight polysomnographic study and a multiple sleep latency test.A total of 124 subjects including 56 patients and 68 controls frequency-matched for age and sex were included. Multivariate analysis revealed that patients had significantly shorter total sleep time than controls (p = 0.01), lower sleep efficiency (p = 0.001) and increased REM latency (p = 0.007). In patients, multivariate analysis showed that reduced total sleep time was significantly associated with increased age (p = 0.001) and increased levodopa dose (p = 0.032). The mean Insomnia Severity Index was higher in PD patients (9.0±7.1) compared to controls (3.3±3.9, p<0.001). The mean Epworth Sleepiness Scale score was higher in PD patients (9.3±5.9 vs. 5.7±4.8, p<0.001). Nocturnal arousals, obstructive sleep apnea, periodic leg movements and objective abnormal sleepiness were not increased in our patients.

Conclusions/Significance

Our case-control polysomnographic study, the first-ever performed in an Asian population, revealed altered sleep architecture and reduced sleep in PD patients compared to controls. Reduced total sleep time was associated with increased age and levodopa dose. However, nocturnal arousals, primary sleep disorders and abnormal sleepiness were not increased in our PD patients suggesting that ethnic/genetic differences may be a factor in the pathophysiology of these conditions.     

Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

Objectives

To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson''s Disease.

Methods

A retrospective study of genetic Parkinson''s diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated.

Results

Scans were available from 37 cases of monogenetic Parkinson''s disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). The asymmetry of radioligand uptake for Parkinson''s disease with GBA or LRRK2 mutations was greater than that for Parkinson''s disease with alpha synuclein, PINK1 or Parkin mutations.

Conclusions

The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss.