A susceptibility locus for Parkinson's disease maps to chromosome 2p13.

Parkinson's disease (PD) is a common degenerative neurologic disorder, which is pathologically characterized by a selective degeneration of dopaminergic neurons of the substantia nigra pars compacta, and the presence of characteristic eosinophilic inclusions, known as Lewy-bodies in affected brain areas. The cause of PD is unknown but, in recent years, genetic factors have been implicated in the aetiology of the disease. Firstly, clinico-genetic, epidemiologic and twin studies revealed inheritable effects and questioned earlier studies which had denied such influences. Secondly, several family studies suggested autosomal-dominant inheritance of syndromes which, to variable degrees, resembled sporadic PD clinically and in some cases also neuropathologically. Recently, a disease locus has been mapped to chromosome 4q21-22 in a large Mediterranean pedigree, in which disease expression is clinically and pathologically within the spectrum of sporadic PD; being atypical only for a relatively young mean age at onset of 46 years and rapid course of 10 years from onset to death. In affected individuals of this family and of three unrelated Greek kindreds, a putative disease-causing mutation has been identified in the gene encoding alpha-synuclein. With the first variant being defined, genetic heterogeneity has become apparent, as in other families parkinsonism was not linked to the 4q-locus and was not associated with the alpha-synuclein mutation (unpublished data). We describe a different genetic locus that appears to be involved in the development of parkinsonism closely resembling sporadic PD including a similar mean age of onset (59 years in the families, 59.7 years in sporadic PD; ref. 12). This locus was detected in a group of families of European origin. In two of these families, there is genetic evidence for a common founder. The penetrance of the mutation appears to be low, most likely below 40%. This is compatible with a possible role of this locus not only in familial, but also in typical (sporadic) PD.

m-Hydroxyphenylacetic acid formation from L-dopa in man: suppression by neomycin.

The increased excretion of m-hydroxyphenylacetic acid in the urine of patients with parkinsonism being treated with L-dopa was reduced by gut sterilization with neomycin. The p-de-hydroxylation step is thus brought about solely by the action of gut flora; the pathway is unlikely to be involved in the events within the brain leading to the therapeutic benefit effected by L-dopa.

Hydroxylase cofactor activity in cerebrospinal fluid of normal subjects and patients with Parkinson's disease.

A method for measuring hydroxylase cofactor activity in human cerebrospinal fluid is described. The hydroxylase cofactor content of cerebrsopinal fluid from Parkinsonian patients is approximately 50 percent that of normal subjects. A significant correlation between hydroxylase cofactor and the concentration of homovanillic acid in the cerebrospinal fluid was observed.

Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease.

The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson's disease (PD). Little is known, however, about the mechanism underlying the placebo effect. Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography, we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo. Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system.

The natural history of neurological manganism over 18 years.

We investigated the clinical features and progression of four patients with chronic manganese intoxication, 18 years after cessation of exposure. Because the results were to be compared with previous observations, we employed the same scoring system. The clinical manifestations were foot dystonia, wide based gait, rigidity, and difficulty in walking backwards. Resting tremor was rarely seen, but tongue tremor was found in 2 patients. The asymmetry initially present in 2 patients persisted 18 years later. Measurements had previously revealed rapid progression in the initial 10 years. We found a plateau over the following decade.

Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition.

The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors.

Disposition of oral lisuride in Parkinson's disease.

The single and multiple oral dose plasma kinetics of lisuride were followed by a recently developed radioimmunoassay method in 11 patients with Parkinson's disease. A very wide range of plasma drug concentrations resulted from a single dose of 300 micrograms, as reflected in large interindividual differences in peak concentration (0.27 to 3.30 ng/ml) and AUC after the initial dose (43.1 to 617 ng X min/ml). Absorption was rapid, with a mean time to peak of 39 min. Only 0.05% of the dose was excreted unchanged in urine in 24 hr. There was a 110% increase in apparent oral clearance after 2 to 4 wk of treatment.

Interactions of levodopa with inhibitors of monoamine oxidase and L-aromatic amino acid decarboxylase.

Drug interactions between levodopa, tranylcypromine, and carbidopa have been studied in 4 patients with idiopathic parkinsonism. Pressor responses were induced by a combination of levodopa and tranylcypromine. These hypertensive reactions were inhibited by carbidopa, indicating that they are mediated at the periphery. Very small doses of levodopa induced an improvement in parkinsonism when patients were concomitantly taking carbidopa and tranylcypromine, but adverse reactions were prominent.

Compensatory mechanisms in degenerative neurologic diseases. Insights from parkinsonism.

In animal models of parkinsonism, the ability to lose a substantial proportion of dopaminergic neurons without behavioral deficits does not derive from other systems taking over function of the dopaminergic pathway. The surviving nigrostriatal projection increases both the rate of synthesis and the release of dopamine, as compensatory adjustments. This capacity allows at least a fivefold rise in dopamine delivery per neuron, and this enhancement is potentiated further by receptor up-regulation. Decreased reuptake, due to loss of nerve endings, may also lead to augmented occupancy of dopamine receptors, and so constitute yet another compensatory mechanism. In humans, positron emission tomography has revealed subclinical impairment of the dopaminergic nigrostriatal pathway in subjects at risk for parkinsonism caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Lytico-Bodig (the amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam). However, the separation of patients with clinically overt idiopathic parkinsonism from controls is less marked in vivo (by positron emission tomography) than in postmortem analysis (by neurochemical assay). This disparity may be attributable to the reduction in the number of nigrostriatal nerve endings, leading, in vivo, to a relative increase of extracellular dopamine because active reuptake into the nerve endings is an important mechanism for removing dopamine from the synaptic cleft. In contrast, in a postmortem setting, dopamine that is not sequestered in the storage vesicles of nerve endings is readily available for biochemical degradation during the interval between death and brain analysis. Finally, it is also possible that differences may derive, in part, from dissimilar kinetic systems for handling exogenous and endogenous levodopa.

Bromocriptine in Huntington chorea.

Following a recent report that apomorphine hydrochloride alleviates the involuntary movements of Huntington chorea, we have investigated another dopamine receptor agonist, bromocriptine, in this disease. A double-blind crossover study in six patients showed that rather than improving chorea, bromocriptine induced an exacerbation. This finding supports the view that choreatic movements correlate with overactivity in dopaminergic systems.

Parkinsonism with 'on-off' phenomena. Intravenous treatment with levodopa after major abdominal surgery.

Continuous intravenous infusion of levodopa was used for eight days to manage a parkinsonian patient with "on-off" fluctuations who underwent abdominoperineal resection for carcinoma of the rectum. Reasonable control of parkinsonism was obtained initially with small doses of levodopa, but more than 4 g daily were eventually required. No adverse effects on cardiac rhythm, blood pressure, or gastrointestinal function occurred. Frequent adjustment of levodopa dosage was necessary in view of continuing "on-off" fluctuations. Severe akinesia, which can cause dysphagia, respiratory complications, and venous stasis in the legs, can benefit from this method of management after major abdominal surgery in a patient with advanced parkinsonism.

Effect of an opiate antagonist on movement disorders.

Animal experiments suggest that opiate peptides might play a role in extrapyramidal function. This hypothesis was tested by administering the opiate antagonist, naltrexone, in doses sufficient to antagonize exogenous opiates, to patients with parkinsonism and Huntington's disease. No improvement in the clinical features of either disorder was noted.

Positron emission tomography in progressive supranuclear palsy.

Positron emission tomography with 6-[18F]fluoro-L-dopa (6-FD) provides in vivo information on the function of nigrostriatal dopaminergic neurons. We used 6-FD and positron emission tomography to investigate the integrity of the nigrostriatal system in seven patients with progressive supranuclear palsy. All patients had axial hypertonia, vertical gaze palsy, and parkinsonian features. Dementia, pyramidal signs, and ataxia were seen in varying proportions. We analyzed the scans with a graphic method to calculate a steady-state 6-FD uptake rate constant for the whole striatum. Results were compared with those obtained in seven age-matched controls. As a group, the patients with progressive supranuclear palsy had reduced 6-FD uptake constants. The 6-FD uptake constant correlated inversely with the duration of the disease. Normal positron emission tographic findings in one patient with the shortest duration of symptoms suggests that in early progressive supranuclear palsy, parkinsonism may relate to dysfunction distal to the dopaminergic neurons.

Chronic manganese intoxication.

We report six cases of chronic manganese intoxication in workers at a ferromanganese factory in Taiwan. Diagnosis was confirmed by assessing increased manganese concentrations in the blood, scalp, and pubic hair. In addition, increased manganese levels in the environmental air were established. The patients showed a bradykinetic-rigid syndrome indistinguishable from Parkinson's disease that responded to treatment with levodopa.

Cerebral glucose metabolism in Parkinson's disease with and without dementia.

Although cognitive impairment is commonly associated with Parkinson's disease, the relative importance of cortical and subcortical pathologic changes to the development of dementia is controversial. Characteristic abnormalities in cortical glucose metabolism have been reported previously in Alzheimer's disease, a disease in which cortical changes predominate. We measured cerebral glucose metabolism with positron emission tomography in 20 control subjects and in 14 patients with PD with mental status ranging from normal to severely demented to determine whether changes in cortical glucose metabolism occur in early PD and whether the degree and pattern of metabolic change relate to the severity of dementia. The patients were divided into demented and nondemented groups according to the results of neuropsychological assessment. Age-adjusted covariance analyses were performed, since the age distribution varied between groups. The nondemented patients with PD showed widespread cortical glucose hypometabolism without any selective temporoparietal defects. The pattern of glucose hypometabolism seen in the demented patients with PD resembled that described in patients with Alzheimer's disease; ie, there was a global decrease in glucose metabolism, with more severe abnormalities observed in the temporoparietal regions.

Initiating treatment for idiopathic parkinsonism.

The initial decision in the management of idiopathic parkinsonism is whether any pharmacotherapy is indicated. There is no conclusive evidence that treatment is helpful before symptoms start to affect the patient's life, although some neurologists believe that deprenyl, also known as selegiline, could be useful. Once functional deficits begin to interfere with the patient's work or social activities, treating symptoms becomes appropriate. Anticholinergics and amantadine can be used, but their limited benefit is often accompanied by unacceptable adverse effects. Dopaminomimetics are the most satisfactory medications, including levodopa and such artificial dopamine agonists as bromocriptine, pergolide, or lisuride.

Studies with bromocriptine. Part 1. "On-off" phenomena.

A dopaminergic agonist, bromocriptine, has been studied in patients with idiopathic parkinsonism complicated by severe "on-off" phenomena induced by levodopa. In a "blind" self-evaluating within-patient comparison, fluctuations in clinical state still occurred when levodopa (with or without carbidopa) was replaced with bromocriptine, but they were significantly reduced in frequency. The observation that on-off phenomena can be induced by bromocriptine complicates interpretation of these episodes in terms of pharmacokinetics of levodopa. There may be variations in receptor sensitivity or alterations in the influence of unidentified neurophysiologic mechanisms that modulate striatal output.

Studies with bromocriptine. Part 2. Double-blind comparison with levodopa in idiopathic parkinsonism.

A double-blind crossover study was performed in 12 patients with idiopathic parkinsonism to compare their response to bromocriptine with their response to previous optimal drug treatment, including levodopa. There was a 26 percent overall improvement with bromocriptine; rigidity, tremor, and facial expression showed the greatest response. Seven of eight patients who were taking levodopa at the beginning of the study was taken off the drug completely. Adverse reactions were transient and dose-dependent. Bromocriptine promises to be an effective new therapeutic agent in the treatment of idiopathic parkinsonism.

Studies with bromocriptine: III. Concomitant administration of caffeine to patients with idiopathic parkinsonism.

Caffeine was administered to six patients with idiopathic parkinsonism in an attempt to potentiate the therapeutic response of bromocriptine, a dopamine (DA) receptor agonist, by inhibition of phosphodiesterase. In a double-blind study at doses of 1,000 mg daily, caffeine failed to enhance the antiparkinsonian action of bromocriptine (40 mg daily) given concomitantly. Although effective in potentiating the action of levodopa and other agonists in animal models of parkinsonism, caffeine is inactive in parkinsonism in man.

Severity of Parkinson's disease and the dosage of bromocriptine.

In view of reports that low-dose bromocriptine (15 mg or less daily) therapy is effective in Parkinson's disease, we undertook a retrospective study of 79 patients with Parkinson's disease to evaluate factors that affect the optimal daily dose of bromocriptine in subjects whose intake of levodopa was decreased as bromocriptine was introduced. Doses of bromocriptine 15 mg or less daily were seldom therapeutic; doses of over 15 mg, up to 30 mg, were appropriate for patients with mild, early disease. Those with more severe symptoms of longer duration usually required larger doses. The optimal daily requirement of bromocriptine was correlated to the severity and duration of the illness, but not to the age of the patient.