Spreading activation of lexical-semantic networks in Parkinson's disease

Although dopamine may act as a neuromodulator of spreading activation within semantic networks, this role of dopamine in lexical networks has not been investigated. Hence, we sought to investigate the effects of Parkinson's disease (PD), which is associated with dopamine depletion, on spreading activation in the lexical networks. Ten Parkinson's disease patients and 11 normal controls performed the controlled oral word association test and the average word frequency for their responses was calculated and used as an index of spreading activation. The PD patients exhibited a lower average word frequency, suggesting increased spreading activation, and a significant relationship between the strength of the initial activation and subsequent extent of spreading activation. Most patients were taking dopaminergic medication and future studies may benefit from examining the changes in spreading activation in lexical networks in PD patients on versus off medication or in healthy controls taking either a placebo or a dopaminergic medication. Although these alterations in lexical access might be related to the reduction of dopamine, one of the hallmarks of PD, these patients also have alterations of other neurotransmitter systems and further studies are needed to more clearly identify the role played by these neurotransmitter on lexical access.     

Semantic priming for coordinate distant concepts in Alzheimer's disease patients

Semantic priming paradigms have been used to investigate semantic knowledge in patients with Alzheimer's disease (AD). While priming effects produced by prime-target pairs with associative relatedness reflect processes at both lexical and semantic levels, priming effects produced by words that are semantically related but not associated should reflect only semantic activation processes. This study was aimed at further investigating automatic semantic priming effects in AD patients when semantically related concepts with little to no lexical association are used. Twenty patients with mild to moderate AD and 20 matched controls (NCs) performed a lexical decision task on 30 concept pairs (15 in the living and 15 in the non-living domain) in an automatic semantic priming paradigm. In order to investigate the relationship between priming alteration and semantic damage, we chose concepts from a database. This allowed us to quantify semantic indexes relative to the structural representation at the feature level.No priming was found in NCs or mild AD patients, probably because feature similarity was insufficient in the concept pairs used. Similar to the hyperpriming observed in previous studies, the appearance of priming in the moderate AD group suggests early semantic damage in which attribute knowledge is partially affected. Furthermore, the finding that priming was predicted by the level of sharing (in the semantic system) of features common to the two concepts in the pairs indicates that the level of redundancy of attribute information is the main factor responsible for resiliency to neurological damage in AD.     

Impaired semantic inhibition during lexical ambiguity repetition in Parkinson's disease

Impairments of semantic processing and inhibition have been observed in Parkinson's disease (PD), however, the consequences of faulty meaning selection and suppression have not been considered in terms of subsequent lexical processing. The present study employed a lexical ambiguity repetition paradigm where the first presentation of an ambiguity paired with a target biasing its dominant or subordinate meaning (e.g., bank - money or bank - river) was followed after several intervening trials by a presentation of the same ambiguity paired with a different target that biases the same (congruent) or a different (incongruent) meaning to that biased on the first presentation. Meaning dominance (dominant or subordinate weaker meanings) and interstimulus interval (ISI) were manipulated. Analyses conducted on the second presentation indicated priming of congruent meanings and no priming for the incongruent meanings at both short and long ISIs in the healthy controls, consistent with suppression of meanings competing with the representation biased in the first presentation. In contrast, the PD group failed to dampen activation for the incongruent meaning at the long ISI when the first presentation was subordinate. This pattern is consistent with an impairment of meaning suppression which is observed under controlled processing conditions and varies as a function of meaning dominance of the first presentation. These findings further refine our understanding of lexical-semantic impairments in PD and suggest a mechanism that may contribute to discourse comprehension impairments in this population.     

多巴丝肼片合用多巴胺受体激动剂治疗帕金森病临床疗效观察

目的 研究多巴丝肼片合用普拉克索或吡贝地尔的疗效与安全性. 方法 选择自2008年8月至2010年1月在福建医科大学附属第一医院神经内科门诊接受治疗的40例PD患者,根据治疗药物的不同分为多巴丝肼片+普拉克索片组(普拉克索组)和多巴丝肼片+泰舒达组(泰舒达组),每组20例.经12周联合用药治疗后,以统一帕金森病评定量表(UPDRS)各部分评分相对于基线(治疗前评分)的变化为指标评估疗效.同时监测血压,观察患者不良反应,比较2组治疗方案的安全性. 结果 经12周治疗后2组UPDRS各项评分相对基线均有下降,差异有统计学意义(P＜0.05).普拉克索组UPDRS-Ⅰ(精神、行为和情感)评分、UPDRS-Ⅳ(治疗的并发症)评分较吡贝地尔组评分下降更多,差异有统计学意义(P＜0.05).普拉克索组临床总有效率为80％,泰舒达组临床总有效率为75％,差异无统计学意义(P＞0.05).2组药品不良反应发生率分别为55％和70％,差异无统计学意义(P＞0.05). 结论 普拉克索或吡贝地尔与多巴丝肼合用治疗PD可获得较显著的近期疗效;在改善PD患者精神、行为和情感及运动波动并发症方面的疗效,普拉克索优于吡贝地尔.     

Parkinson's disease,melanoma, and levodopa

Zusammenfassung Das gleichzeitige Vorkommen einer Parkinsonschen Krankheit und eines Melanoms ist selten. Es wurden bisher 5 Fälle publiziert, und in der vorliegenden Arbeit ein sechster. Obwohl diese Koinzidenz der beiden Erkrankungen auch auf reinem Zufall beruhen könnte, mahnt doch der zeitliche Zusammenhang zwischen Beginn der Levodopa-Therapie und der Zunahme des Wachstums des Melanomgewebes zur Vorsicht bei der Verwendung von Levodopa zur Behandlung eines Parkinsons bei Patienten mit bekanntem Melanom.     

Excessive daytime sleepiness and on-road driving performance in patients with Parkinson's disease

The impact of excessive daytime sleepiness (EDS) on road test performance was examined in patients with Parkinson's disease (PD). Twenty-one patients with PD completed the Epworth Sleepiness Scale (ESS) and an on-road driving test. Five participants had EDS according to their self-report on the ESS. Neither EDS nor PD medications were associated with on-road driving performance. These findings suggest that in this pilot study EDS did not impair PD patients' driving skills on a formal driving evaluation.     

司来吉兰联合复合多巴治疗帕金森病的有效性和安全性

目的 探讨司来吉兰联合复合多巴治疗帕金森病的疗效和安全性.方法 将89例帕金森病患者随机分为对照组(45例)和治疗组(44例),对照组患者采用复合多巴等药物治疗,治疗组患者加用司来吉兰治疗,6个月为1个观察周期.于用药前及用药后1、3、6个月采用PD统一评分量表(UPDRS)对两组患者进行疗效评定,并观察其不良反应.结果 治疗组患者治疗1个月时与治疗前相比,除UPDRSⅢ评分降低外(P＜0.01),UPDRSⅠ、Ⅱ、Ⅳ评分变化均无统计学差异(均P＞0.05);治疗3、6个月时与治疗前比较,其UPDRSⅠ～Ⅳ评分均下降(P＜0.01);治疗3、6个月时与治疗1个月时比较,UPDRS Ⅰ、Ⅲ、Ⅳ评分降低均降低(P＜0.01,P＜0.05);治疗6个月时与治疗3个月时相比,其UPDRS Ⅰ～Ⅳ评分均无统计学差异(P＞0.05).治疗3、6个月时,治疗组UPDRSⅠ～Ⅳ评分均明显低于对照组(P＜0.01,P＜0.05).观察期内,两组患者未出现严重不良反应.结论 司来吉兰联用复合多巴可有效改善帕金森病症状,且耐受性好,不良反应少.     

Rule-based category learning in patients with Parkinson's disease

Measures of explicit rule-based category learning are commonly used in neuropsychological evaluation of individuals with Parkinson's disease (PD) and the pattern of PD performance on these measures tends to be highly varied. We review the neuropsychological literature to clarify the manner in which PD affects the component processes of rule-based category learning and work to identify and resolve discrepancies within this literature. In particular, we address the manner in which PD and its common treatments affect the processes of rule generation, maintenance, shifting and selection. We then integrate the neuropsychological research with relevant neuroimaging and computational modeling evidence to clarify the neurobiological impact of PD on each process. Current evidence indicates that neurochemical changes associated with PD primarily disrupt rule shifting, and may disturb feedback-mediated learning processes that guide rule selection. Although surgical and pharmacological therapies remediate this deficit, it appears that the same treatments may contribute to impaired rule generation, maintenance and selection processes. These data emphasize the importance of distinguishing between the impact of PD and its common treatments when considering the neuropsychological profile of the disease.     

Experience with selegiline and levodopa in advanced Parkinson's disease

We compared the results of treatment with selegiline (deprenyl, Eldepryl) in 17 patients with advanced Stage 4 Parkinson Disease (PD) who were on levodopa (as Sinemet) with 65 Stage 2 or 3 patients with early PD who were also on levodopa. The first group consisted of 17 patients with advanced Stage 4 PD without response fluctuations ("wearing off" or "on off" phenomena). Their mean age was 72.1 ± 7.5 years, their mean duration of PD was 7.4 ± 3.2 years. The second group consisted of 65 patients with Stage 2 or 3 PD who had recently been started on levodopa. Their mean age was 63 ± 12.1 years, their mean duration of PD was 7.4 ± 3.2 years. The mean dose of selegiline was 10.0 ± 1.8 mg per day (range 5–20 mg). The mean duration of treatment was 1.5 ± 0.8 years.
During the four years of observation 55.3 ± 8.0% of the Stage 2 or 3 patients improved while only 14.3 ± 13.5% of the Stage 4 patients improved. This difference was significant (p<0.05). During this time 22.0 ± 6.7% of the Stage 2 or 3 patients worsened and 60.7 ± of the Stage 4 patients worsened. This degree of worsening was significant (p<0.05). Adverse effects were minor and reversible.
Our observations suggest that selegiline is more effective (higher percent of patients improving, lower percent of patients worsening) when it is added earlier with patients on levodopa than when it is added later.     

Mortality of patients with parkinson's disease treated with levodopa

Summary The effect of levodopa on the mortality of patients with Parkinson's disease was investigated in 349 patients treated with levodopa or levodopa combined with a decarboxylase inhibitor during 1969–1975 inclusive. During the study period, 61 patients died. The expected mortality was 32.99 resulting in a ratio of actual to expected deaths of 1.85. The excess mortality was accounted for by patients with a severe disease at entry and especially, by the less favorable effect of levodopa treatment than in the living patients. In comparison with the prelevodopa era, the reduction of mortality and the increase of life expectancy of patients with Parkinson's disease during levodopa treatment possibly reflect the decrease of the early mortality due to Parkinson's disease.

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Zusammenfassung Die Auswirkung der Levodopa-Behandlung auf die Mortalität von Parkinson-Patienten wurde anhand einer Serie von 349 Fällen untersucht, welche in den Jahren 1969–1975 einerseits mit L-Dopa, andererseits mit L-Dopa zusammen mit Decarboxylasehemmern behandelt wurden. Während der Beobachtungsperiode verstarben 61 Patienten. Die erwartete Mortalität hätte 32,99 betragen müssen, was eine Relation von tatsächlicher zu erwarteter Mortalität von 1,85 ergibt. Für die höhere Mortalität waren Fälle verantwortlich mit schweren Krankheitserscheinungen bei Beginn der Therapie und im besondern auch mit einem geringeren Effekt der L-Dopa-Therapie als bei den überlebenden Patienten. Verglichen mit den Beobachtungen vor Einführung der L-Dopa-Therapie beruht wohl die Verminderung der Mortalität und die erhöhte Lebenserwartung von Parkinson-Patienten unter L-Dopa auf der Abnahme der Frühtodesfälle durch die Parkinson'sche Krankheit.

     

阿尔兹海默病患者语义记忆障碍特征性研究

目的 探讨阿尔兹海默病(Alzheimer's disease, AD)患者语义记忆障碍的特点,揭示语义知识在大脑中组织的性质。方法 对43例AD患者及28例正常对照者进行一般认知功能测评和语义记忆评估。语义记忆评估选用常见的有生命类及无生命类物体,进行口头图片命名、口头声音命名、图片关联匹配、词语关联匹配测试。统计每一例被试对物体名称和物体语义关联匹配的正确比例,对数据进行群组分析和个体分析。结果 与正常对照组相比,AD组对有生命物体和无生命物体的名称及语义关联匹配均有损伤。10例患者在有生命物体的语义任务上的成绩显著差于在无生命物体的语义任务上的成绩,而另外6例患者在无生命物体的语义任务上的成绩显著差于在有生命物体的语义任务上的成绩。结论 AD患者存在语义记忆障碍,部分AD患者可出现语义范畴特异性损伤,且可出现语义障碍的范畴双分离现象。这表明有生命物体和无生命物体范畴在大脑内相对独立表征,与大脑中语义知识的分布式表征理论一致。     

Controlled-release levodopa/benserazide (Madopar HBS): clinical observations and levodopa and dopamine plasma concentrations in fluctuating parkinsonian patients

Summary In five levodopa (l-dopa)-treated patients with Parkinson's disease with severe fluctuations of motor performance, plasma l-dopa as well as dopamine levels were measured during 2 days, first under optimal standard l-dopa with peripheral decarboxylase inhibitor (PDI) and then after a dose adjustment period using slow-release l-dopa/benserazide (Madopar HBS) in an open inpatient trial. Three patients benefited from the slow-release preparation; two patients deteriorated with a tendency to have an unpredictable response, a delay to turn on with the first dose in the morning, as well as an increase in dyskinesia corresponding to l-dopa cumulation during the day. These problems were subsequently also seen during the follow-up period of 1 year in those patients who benefited from Madopar HBS as inpatients. This might indicate that patient compliance is more difficult with the new formulation. After 1 year all patients had returned to their previous standard l-dopa/PDI treatment. l-Dopa levels continued to fluctuate, but to a lesser degree with Madopar HBS. The equivalent l-dopa dosage had to be increased by 56% (29–100%) with Madopar HBS while mean dopamine levels increased in four patients (by 47–257%) without the occurrence of peripheral side-effects. This implies that with the new formulation more l-dopa is metabolized to dopamine and explains the necessity to increase the equivalent l-dopa dosage.     

Problems and unanswered questions concerning levodopa treatment in Parkinson's disease

Abstract– The main problems in long-term treatment of Parkinson's disease with levodopa are: 1. progressive decline in efficacy; 2. psychiatric complications; 3. the development of motor fluctuations. These are discussed, and important unanswered questions addressed, including when levodopa therapy should be started and at what dose; whether levodopa is in fact harmful in any way; what is the pharmacological role of 0-methyl-dopa, present in such high concentrations; and the best management of motor fluctuations.     

Early selegiline therapy reduces levodopa dose requirement in Parkinson's disease

In an earlier report of our placebo-controlled selegiline trial on de novo parkinsonian patients, we have shown that the need to start additional levodopa therapy is significantly postponed by using selegiline monotherapy. Now we report the two-year interim results of the double-blind continuation of the trial in 44 patients after the introduction of levodopa to the earlier therapy with placebo or selegiline (21 and 23 patients, respectively). The clinical disability was assessed by three rating scales. The daily dose of levodopa needed to maintain an optimal condition had to be increased progressively up to a 52% higher level in the placebo group than in the selegiline group (543 ± 150 and 358 ± 117 mg, respectively, p<0.001). The number of daily doses of levopoda was also statistically significantly higher in the placebo group during the 24 months' observation period (p<0.01). The ratio of levodopa doses that was expected to stay the same contrarily significantly increased suggesting that selegiline would, besides having the levodopa potentiating effect, also have a beneficial influence on the progression of the basic cerebral dopamine deficiency. The combination of selegiline and levodopa was well tolerated, and the adverse event profiles did not differ from each other. In conclusion, early selegiline therapy allows a significant saving in the subsequent levodopa dosage. This saving seems to become even stronger along with the treatment time.     

Switching between abstract rules reflects disease severity but not dopaminergic status in Parkinson's disease

This study sought to disambiguate the impact of Parkinson's disease (PD) on cognitive control as indexed by task set switching, by addressing discrepancies in the literature pertaining to disease severity and paradigm heterogeneity. A task set is governed by a rule that determines how relevant stimuli (stimulus set) map onto specific responses (response set). Task set switching may entail reconfiguration in either or both of these components. Although previous studies have shown that PD patients are impaired at switching between stimuli, in the present study not all patients were impaired at switching entire task sets, that is, both stimulus and response sets: compared with controls, patients with unilateral signs (Hoehn & Yahr Stage I) demonstrated intact switching, even following withdrawal from dopaminergic medication, while bilaterally affected Stage II patients were impaired. The parametric measure of Unified Parkinson's Disease Rating Scale (UPDRS) score predicted increasing switch costs within the patient group. These findings suggest that switching entire task sets may be a function of extrastriatal, possibly non-dopaminergic pathology which increases as the disease progresses.     

Cerebral atrophy and long-term response to levodopa in Parkinson's disease

Summary In 92 parkinsonian patients (42 men, 50 women) aged from 37–79 years (mean 62.8) the impact of cerebral atrophy as assessed by computed tomography on the course of the clinical symptomatology under levodopa during a period of 1 to 5 years was investigated. It could be shown that patients suffering from medium to severe degrees of atrophy—independent of its special location—have a less favorable response than those with normal CT findings. The data do not allow a definite decision whether cortical artrophy or ventricular enlargement are of major importance. At any rate, the width of the third ventricle seems to have no influence on the course of the clinical symptoms. After 3 years of levodopa treatment a dissociation between cerebral atrophy and therapeutic effectiveness can be observed.

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Zusammenfassung An 92 Parkinsonkranken (42 Männer, 50 Frauen) im Alter von 37–79 Jahren (mittleres Alter 62,8 J.) wurde der Einfluß computertomographisch erfaßter hirnatrophischer Veränderungen auf den Verlauf der klinisch-neurologischen Symptomatik unter L-Dopa während einer Beobachtungszeit von 1–5 Jahren untersucht. Die Ergebnisse zeigen, daß Kranke mit einer Hirnatrophie mittleren bis schweren Grades — unabhängig von der jeweiligen Lokalisation — einen geringeren Besserungsgrad aufweisen als solche mit einem normalen CT-Befund. Die Daten erlauben keine eindeutige Entscheidung darüber, ob die kortikale Atrophie oder die Ventrikelerweiterung von größerer Wichtigkeit sind. Keinen Einfluß auf den Verlauf scheint die Weite des 3. Ventrikels zu haben. Nach dem 3. Behandlungsjahr kommt es zu einer Dissoziation der Beziehungen zwischen Hirnatrophie und Behandlungseffekt.

     

Genetic factors involved in the pathogenesis of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by a loss of nigrostriatal dopaminergic neurons. Recently, PD research has been stimulated by the identification of genes that are implicated in rare familial forms of PD. However, despite these discoveries, the primary cause of PD is still unclear. Various pathogenic mechanisms may be involved including mitochondrial dysfunction, proteasomal dysfunction/protein aggregation, oxidative damage, environmental factors and genetic disposition. Furthermore, dopamine has also been implicated in contributing to the pathogenesis of PD. This review will focus on the genes that have been identified to be associated with PD and how they may impair dopamine metabolism. Understanding the role of these PD-related genes in dopamine neurobiology may provide insight into the underpinning pathogenic mechanisms of PD.     

Visuomotor priming effects in Parkinson's disease patients depend on the match between the observed and the executed action

Evidence exists that action observation activates the same cortical motor areas that are involved in the performance of the observed actions. An untested idea is whether subcortical structures such as the basal ganglia play a role in the coding of other people's actions. This study used kinematics to examine how Parkinson's disease patients react to the observation of an action which they were subsequently requested to perform. In each trial a model and an observer, which could be either a Parkinsonian patient or a neurologically healthy participant, were seated facing each other. The model was requested to grasp a stimulus (action condition), to perform a kicking action towards the stimulus (control-action condition), and to not perform any action (control condition). The task for the observer was always to grasp the stimulus after having watched the model performing her task. Results show that Parkinson's disease patients did show facilitation effects only when the model was a Parkinsonian patient. Whereas, neurologically healthy participants’ movements were facilitated following the observation of either the Parkinsonian and the healthy model grasping the object. No facilitation effects were found for both the control and the control-action conditions. The fact that normal visuomotor priming takes place in PD patients when the observed action matches with what they can perform suggests that basal ganglia might not be necessary for it. However, damage to the basal ganglia might become relevant when such a match does not occur. In such circumstances, a damage to these structures might prevent the deployment of additional activity which might be necessary to influence cortical functions related to the representations of observed actions.     

Dopamine transporter immunoreactivity in peripheral blood lymphocytes in Parkinson's disease

Summary. There is increasing interest in the identification of biological markers for the early diagnosis of Parkinson's disease (PD). Previous studies indicate changes of dopamine content, tyrosine hydroxylase immunoreactivity and dopamine receptors in peripheral blood lymphocytes (PBL) in PD. Here we demonstrate a reduction of dopamine transporter immunoreactivity in PBL in the early clinical stages of the disease. These findings contribute to our understanding of the peripheral dopamine system in PD. Received November 16, 2000; accepted March 19, 2001