Changes in taste under L-DOPA therapy

Summary Changes in taste is a side-effect of L-DOPA therapy. This side-effect is about five times less frequent when L-DOPA is administered with a decarboxylase inhibitor; in the absence of a decarboxylase inhibitor higher dose of L-DOPA must be given. The data suggest that the cause of changes in taste due to L-DOPA is extracerebral rather than intracerebral.

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Zusammenfassung Störungen des Geschmackssinnes gehören zu den Nebenwirkungen der L-DOPA-Therapie. Diese Erscheinung ist etwa fünfmal weniger häufig wenn L-DOPA zusammen mit einem Dekarboxylasehemmer gegeben wird. Die eigenen Untersuchungen lassen darauf schließen, daß die Geschmackstörungen bei L-DOPA-Therapie einen extracerebralen und nicht einen intracerebralen Angriffspunkt haben.

     

Cardiovascular reflexes and autonomic dysfunction in parkinson's disease

Summary Cardiovascular reflexes were analysed in a group of 20 patients suffering from Parkinson's disease and in 12 age-matched healthy subjects, in order to ascertain the incidence and degree of autonomic dysfunction. The following were measured: heart rate variation during normal breathing, postural change (30/15 ratio) and during the Valsalva manoeuvre; blood pressure variation after standing. These measurements were taken at least 12 h after therapy had been withdrawn and were repeated after therapy had been resumed. Significant changes in the different heart rate variation indices were found in the parkinsonian patients which correlated with the duration and severity of the extrapyramidal symptomatology. After standing the patients showed a significant drop in blood pressure, when compared respectively with their base values and with the response in controls. Anticholinergic drugs had no significant effect on the heart rate variation indices, whereas antiparkinsonian therapy seems to have contributed to the drop in blood pressure after standing.     

左旋多巴诱发羟自由基增高的机制与防治

目的探讨左旋多巴治疗帕金森病诱发羟自由基增高的机制与防治的药物。方法使用脑微透析方法在帕金森病大鼠模型的活体内，用高压液相电化学检测法测定羟自由基和多巴胺的水平。结果发现在注射左旋多巴后，帕金森病动物模型的纹状体细胞外液多巴胺和羟自由基同步地明显增高，而同样的治疗在正常的动物没有引起任何的明显增高。在使用多巴胺高亲和力重摄取位点的阻断剂ＧＢＲ１２９０９后，左旋多巴治疗正常动物也引起了类似于帕金森病动物的变化。实验结果没有发现使用单胺氧化酶Ｂ的抑制剂能防止左旋多巴治疗后引起的羟自由基的增高。结论左旋多巴治疗可能仅在帕金森病人的脑内相应部位造成羟自由基的增高，而帕金森病多巴胺高亲和力重摄取位点的丧失可能是造成羟自由基增高的原因     

Direction-specific postural instability in subjects with Parkinson's disease

The purpose of this study was to determine whether and why subjects with Parkinson's disease (PD) have greater instability in response to specific directions of perturbations than do age-matched control subjects and how instability is affected by stance width. This study compared postural responses to 8 directions of surface translations in PD subjects and age-matched control subjects while standing in a narrow and wide stance. PD subjects were tested in their practical OFF state. A postural stability margin was quantified as the difference between peak center of pressure (CoP) and peak center of mass (CoM) displacement in response to surface translations. The control subjects maintained a consistent stability margin across directions of translations and for both narrow and wide stance by modifying rate of rise of CoP responses. PD subjects had smaller than normal postural stability margins in all directions, but, especially for backwards sway in both stance widths and for lateral sway in narrow stance width. The reduced stability margin in PD subjects was due to a slower rise and smaller peak of CoP in the PD subjects than in control subjects. Lateral postural stability was compromised in PD subjects by lack of trunk flexibility and backwards postural stability was compromised by lack of knee flexion, resulting in excessive displacements of the body CoM. Stability margins in PD subjects were related to their response on the pull test in the Unified Parkinson's Disease Rating Scale. Thus, PD patients have directionally specific postural instability due to an ineffective stiffening response and inability to modify their postural responses for changing postural demands related to direction of perturbation and initial stance posture. These results suggest that the basal ganglia, in addition to regulating muscle tone and energizing postural muscle activation, also are critical for adapting postural response patterns for specific biomechanical conditions.     

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.

     

The effect of vision on postural strategies in Prader-Willi patients

The aim of this study was to quantify the role of visual contribution in patients with Prader-Willi syndrome (PWS) on balance maintenance using a force platform. We enrolled 14 individuals with PWS free from conditions associated with impaired balance, 44 obese (OG) and 20 healthy controls (CG). Postural sway was measured for 60 s while standing on a force platform (Kistler, CH; acquisition frequency: 500 Hz) integrated with a video system. Patients maintained an upright standing position with Open Eyes (OE) and then with Closed Eyes (CE). The ratio between the value of the parameter under OE and CE conditions was measured. Under OE condition PWS and OG were characterized by higher postural instability than CG, with the PWS group showing poorer balance capacity than OG. The Romberg ratio showed that while OG and CG had lower balance without vision, PWS maintained the same performance changing from OE to CE. The integration of different sensory inputs appears similar in OG and CG with higher postural stability under OE than CE. Balance in PWS is not influenced by the elimination of visual input.     

Chronic L-DOPA treatment increases extracellular glutamate levels and GLT1 expression in the basal ganglia in a rat model of Parkinson's disease

There is growing experimental evidence for the implication of glutamate-mediated mechanisms both in the pathophysiology of Parkinson's disease and in the development of dyskinesias with long-term administration of L-3,4-dihydroxyphenylalanine (L-DOPA). However, the impact of this treatment on glutamate transmission in the basal ganglia has been poorly investigated. In this study, we examined the effects of 6-hydroxydopamine-induced lesion of nigral dopamine neurons with or without subsequent chronic L-DOPA treatment on several parameters of glutamate system function in the rat striatum and substantia nigra pars reticulata. All the lesioned animals treated with L-DOPA developed severe dyskinesias. Extracellular glutamate levels, measured by microdialysis in freely moving conditions, and gene expression of the glial glutamate transporter GLT1, assessed by in situ hybridization, were unaffected by dopamine lesion or L-DOPA treatment alone, but were both markedly increased on the lesion side of rats with subsequent L-DOPA treatment. No change in the expression of the vesicular glutamate transporters vGluT1 and vGluT2 was measured in striatum. These data show that chronic L-DOPA treatment leading to dyskinesias increases basal levels of glutamate function in basal ganglia. The L-DOPA-induced overexpression of GLT1 may represent a compensatory mechanism involving astrocytes to limit glutamate overactivity and subsequent toxic processes.     

The deterioration of cardiovascular reflexes in Parkinson's disease

OBJECTIVES: We have investigated the deterioration of cardiovascular reflexes in Parkinson's disease. PATIENTS AND METHODS: In a group of 20 patients with Parkinson's disease (PD) and in a group of 10 age-matched control subjects a battery of cardiovascular reflex (CVR) tests (Valsalva manoeuvre, deep breathing test, handgrip test, orthostatic test) was repeated after 3 years. RESULTS: In PD patients at deep breathing test, at Valsalva manoeuvre and at orthostatic test the heart rate response decreased significantly (P<0.05). The impairment of systolic and diastolic blood pressure response at orthostatic test was significant as well (P < 0.005). At hand grip test no significant changes in heart rate and blood pressure response were found. In control subjects only heart rate response at orthostatic test decreased significantly after 3 years. CONCLUSION: Our results show progression of an impairment of sympathetic and parasympathetic control of the cardiovascular functions in patients with PD over a period of 3 years.     

Effects of intracerebroventricular L-DOPA on caudate unit firing

Single units were recorded bilaterally from the caudate nuclei of cats before and after 50 μl injections of either Merlis solution or L-DOPA (200 μg) dissolved in Merlis into the left lateral cerebral ventricle. After injection of L-DOPA, but not Merlis solution, there was a period of unit silence in both caudates with an onset of about 10 min and a duration of 30–50 min. This period of caudate silence was coincident with a significant reduction of systolic blood pressure and heart rate. Upon resumption of unit firing in caudate, it was found that the interspike intervals on the contralateral side were markedly increased from 30 min-2 hr postinjection while there was no change on the side of injection. The similarity of this response to that following lesions which interrupt the caudate to thalamus pathway unilaterally was discussed. It is suggested that L-DOPA injection may produce this lesion-like effect by altering the firing of caudate output neurons.     

L-DOPA modulation of corpus striatal dopamine and dihydroxyphenylacetic acid output from intact and 6-OHDA lesioned rats

Summary In the present report we examined the differences in in vitro dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) efflux from the corpus striatum (CS) of intact versus 6-hydroxydopamine (6-OHDA) lesioned (in substantia nigra) male rats in response to different doses of two pulse infusions of L-dihydroxyphenylalanine (L-DOPA). In the first experiment, we tested the effects of two 20-min infusions of 5 uM L-DOPA. In the second experiment we repeated this protocol using 50 uM L-DOPA. There was an overall significantly greater output of DA for intact versus 6-OHDA lesioned rats for both doses. Moreover, in Experiment 1, the 5 uM L-DOPA produced a peak DA response to the second infusion which was significantly higher than that of the first infusion in the intact, but not lesioned rats. In Experiment 2, the 50 uM L-DOPA group showed no significant differences in DA output between the two infusions for both intact and lesioned rats. In contrast to DA responses, there were no overall significant differences in DOPAC output between intact and 6-OHDA lesioned rats for both doses. However, for both doses tested, the peak DOPAC output from the second infusion was significantly increased in lesioned, but not intact rats. These data demonstrate that L-DOPA evoked DA and DOPAC output are differentially modulated in intact and 6-OHDA lesioned striatum. The lesions of the striatal dopaminergic system may alter these responses through changes in intraneuronal storage and metabolism of DA following L-DOPA infusion.     

抑郁对帕金森病患者执行功能的影响

目的 探讨抑郁对帕金森病(PD)患者执行功能的影响。方法 对41例PD患者及20例对照组进行整体认知功能、执行功能及抑郁状况的评定。整体认知功能评定使用简易智力状态量表(MMSE); 执行功能评定包括言语流畅性测验(VFT),连线测验(TMT),Stroop字色干扰测验(SCWT),画钟测验(CDT),数字符号替换测试(DSST)及数字广度测试(DST)等; 使用贝克抑郁自评量表(BDI)评估抑郁状态。结果 抑郁组SFT, PFT, DST, DSST, CDT, TMA,TMB, Stroop-B, Stroop-C,SIE评分均差于对照组(P<0.05); 非抑郁组PFT, DST, DSST,TMA,TMB, Stroop-C,SIE评分差于对照组(P<0.05); 与非抑郁组比较,抑郁组SFT, PFT, DST, DSST, TMA, TMB, Stroop-B, Stroop-C, SIE评分较差(P<0.05)。结论 PD患者存在明显的执行功能障碍,抑郁可以明显加重PD患者的执行功能障碍。     

Performance of concurrent non-motor tasks in parkinson's disease

Summary The purpose of the study was to examine the hypothesis that patients with Parkinson's disease have a general inability to cope with concurrent task demands, and that this inability stems from a lack of attentional control of motor and cognitive activities. Performance on a verbal and on a visuospatial memory task was compared with performance on largely identical memory tasks which were combined with concurrent non-motor tasks. As a further index of a possible weakness of the attentional control of cognitive function order memory was assessed and compared with item memory. Both parkinsonian patients and controls showed a decline of memory performance when the concurrent task was introduced, but the degree of decline did not differ between groups. Parkinsonian patients scored worse than controls on both conditions of the verbal memory task and had more intrusions from previous lists in the verbal single task. There was no significant difference between groups in either item or order memory, but in parkinsonians the scores on order memory decreased with advancing illness. It is concluded that patients with Parkinson's disease do not have a general inability to cope with concurrent task demands, but that the results can be interpreted as indicating a weakness of certain aspects of the attentional control of cognitive function.     

The effect of a cognitive task on the postural control of dyslexic children

We explore the influence of a secondary cognitive task on concurrent postural control in dyslexic children. Seventeen children with dyslexia (DYS) were compared with thirteen non-dyslexic children (NDYS). Postural control was recorded in Standard Romberg (SR) and Tandem Romberg (TR) conditions while children, in separate sessions, have to fixate on a target and name simple objects appearing consecutively on a computer screen. The surface, the length and the mean speed of the center of pressure were analyzed; the percentage of correct responses to the cognitive task was also measured. DYS are significantly more unstable than NDYS. The secondary cognitive task significantly decreases the postural stability in DYS only. For both children postural performances in the TR condition is significantly worse than in the SR condition. The percentage of wrong responses to the cognitive task is significantly higher in DYS. Postural instability observed in DYS supports the hypothesis that there is a deficit of automatic integration of visual information and postural control in these children. This result is in line with the U-shaped non linear model showing that a secondary task performed during a postural task leads to an impaired postural stability probably due to focus attention on the cognitive task.     

Peripheral and central inhibitors of catechol-O-methyl transferase: effects on liver and brain COMT activity and L-DOPA metabolism

Summary Inhibitors of the enzyme catechol-O-methyl transferase (COMT) may be useful adjuncts to L-DOPA in the treatment of Parkinson's disease as they offer the possibility of increasing the availability of the amino acid. It is unknown whether a COMT inhibitor which penetrates the blood-brain barrier is preferable to one restricted to extra-cerebral inhibition. We measured liver and brain COMT activity two hours following administration of two COMT inhibitors: entacapone (ENT), mainly peripherally acting, and dinitrocatechol (DNC), peripheral and central acting. As expected, the full spectrum inhibitor DNC (30 mg/kg) induced a near total inhibition of liver and brain COMT activity. Unexpectedly, however, ENT, at 30 mg/kg, produced the same degree of liverand brain COMT inhibition as DNC; using 10 mg/kg, ENT still inhibited both liver and brain COMT activity by 80%. Only at 2.5 and 5 mg/kg did ENT achieve a differential inhibition of liver (80% inhibition) versus brain (10–30% inhibition) COMT activity. In a second series of experiments, we administered ENT (2.5,10, and 30 mg/kg) and DNC (30 mg/kg) to rats and monitored extracellular striatal dopamine and dopamine metabolite levels with cerebral microdialysis both under basal conditions and following L-DOPA/carbidopa administration. No compound modified basal striatal levels of dopamine. ENT at 30 mg/kg (but not 2.5 or 10 mg), as well as DNC, decreased striatal levels of the methylated dopamine metabolite homovanillic acid (HVA). When L-DOPA/carbidopa was administered, dopamine formation was greatest and HVA formation least in animals pretreated with DNC and 30 mg/kg ENT (but not 2.5 or 10 mg/kg ENT). The finding that ENT at doses relatively specific for peripheral enzyme inhibition did not promote dopamine or inhibit HVA formation is most likely due to the 20% residual liver COMT activity present when the inhibitor was used at less than full doses. Our data indicate that DNC and ENT both inhibit striatal HVA formation and increase dopamine formation from exogenously administered L-DOPA. The dopamine promoting effect of ENT is only present, however, at doses which inhibit central as well as peripheral COMT activity.     

The mechanism of perturbation in monoamine metabolism by L-DOPA therapy: in vivo and in vitro studies

Summary In the cerebrospinal fluid of the patients with Parkinson's disease treated with L-DOPA, L-3-O-methyldopa was the major metabolite of administered L-DOPA. Using a dopaminergic cell model, clonal rat phenochromocytoma PC 12h cells, and by microdialysis of the rat striatum it was proved that L-3-O-methyldopa was taken up into monoamine neurons by transport system specific for aromatic L-amino acids and inhibited transport of L-DOPA and other amino acids competitively. L-3-O-Methyldopa depleted allosteric regulation of the biopterin cofactor on activity of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis. Depletion of the allostery may perturb the buffer action of endogenous L-DOPA synthesis that stabilizes dopamine level in the brain. By these mechanisms L-3-O-methyldopa may reduce clinical effectiveness of administrated L-DOPA and be involved in wearing-off phenomenon. L-DOPA inhibited the activity of tryptophan hydroxylase and thus serotonin synthesis, which may be related to psychiatric side-effects in the patients under L-DOPA therapy.     

帕金森病模型的建立及猴自体颈上交感神经节移植后的动态观察

目的：探讨帕金森动物模型的建立及神经节移植后对帕金森病症状的影响。万法：用恒河猴6只经颈内动脉注射MPYP诱发帕金森病,取自体颈上交感神经节移植后观察17个月,肌电图及计算机体层摄影（CT）检查,标本组织学及免疫组织化学观察。结果：用MPTP诱发帕金森病其表现与病人相似,移植神经节后动物症状呈好转－恶化－恢复正常的变化规律,17个月后脑内可见存活的神经节细胞。结论：用MPFP颈内动脉注射是制备帕金森病动物模型的较好办法,自体颈上交感神经节移植后帕金森病症状改善并长期稳定,移植后17个月仍可见存活的神经节细胞。     

Glia protect fetal midbrain dopamine neurons in culture from L-DOPA toxicity through multiple mechanisms

Summary Mesencephalic glia produce soluble factors that protect dopamine neurons from L-DOPA toxicity. The chemical composition of these soluble factors is unknown. We investigated the protective effect against L-DOPA neurotoxicity in midbrain dopamine neurons of fractions of different molecular size of glia conditioned medium and candidate neuroprotective agents produced by glia including neurotrophic factors and antioxidants. Protective effects were evaluated according to the number of tyrosine hydroxylase immunoreactive cells, high affinity dopamine uptake and levels of quinones. Both fractions of glia conditioned medium, smaller and larger than 10kD, protected against L-DOPA, but the fraction of smaller molecular size, that contains small free radical scanvenger molecules, was more effective than the fraction of larger molecular size, that contains large neurotrophic peptides. Among the neurotrophic factors GDNF and BDNF totally prevented L-DOPA neurotoxicity, while NGF and bFGF were less effective. However, only NGF significantly reduced the elevation of quinones induced by L-DOPA. Ascorbic acid, at the concentration found in glia conditioned medium, provided partial protective effect against L-DOPA toxicity. Glutathione, had neurotrophic effects on untreated midbrain dopamine neurons and prevented the effect of L-DOPA. In conclusion, the protective effect against L-DOPA neurotoxicity by glia conditioned medium is mediated by several compounds including neurotrophic factors and small antioxidants.     

恩他卡朋治疗帕金森病的疗效观察

目的观察恩他卡朋辅助复方多巴制剂对帕金森病患者运动症状的影响。方法原发性帕金森病患者28例,均服用复方多巴制剂并在出现症状加重或运动波动时加用恩他卡朋。服药前、后定期行统一帕金森病评分量表(unified parkinson disease rating scale,UPDRS)Ⅱ与Ⅲ评分,观察其副作用,记录每剂复方多巴制剂的起效时间及药效维持时间。结果UPDRSⅡ与Ⅲ评分在服药前分别为15.1±5.1、22.2±8.1,服药1个月后(10.9±2.8;16.4±4.5)、服药3个月后(12.2±3.5;18.8±5.2)均降低(P<0.01)。服药后每剂药物起效时间不变,药效维持时间延长(1.3±0.6)h(P<0.05)。结论恩他卡朋可改善帕金森病患者的运动功能,副作用少,服用安全。