Journal of Neural Transmission - Parkinson's Disease and Dementia Section最新文献

Recent experiments provide evidence that the NMDA-antagonist MK-801 has a locomotor-stimulating effect in monoamine-depleted rodents. These findings are based upon a hypothetical pathway-circuit including the basal ganglia as a model reflecting hypo- and hyperkinetic movement disorders. We have treated 5 patients suffering from Parkinson's disease with the antiepileptic drug "lamotrigine" which does not appear to be an NMDA-antagonist but acts functionally as a glutamate antagonist by inhibition of presynaptic glutamate release.

We studied the effect of amino acid load on L-dopa-induced rotational behavior in rats with unilateral lesion of the nigrostriatal pathway. Pretreatment of rats with an ingestion of high concentration of amino acids significantly reduced the number of rotations induced by subcutaneously injected L-dopa. These results provide the experimental basis for clinical observations that dietary protein affects the response to L-dopa in parkinsonian patients.

Aim of this study was the characterization of the circadian melatonin profile in de novo Parkinson patients (N = 9, age 60.0 +/- 3.2 years, mean +/- SEM) and the comparison of these profiles with those of controls and Parkinson patients treated with l-dopa/decarboxylase inhibitor (l-dopa/DCI). We collected 14 venous blood samples during a period of 24 hours and measured the serum melatonin levels by a radioimmuno assay. De novo Parkinson patients displayed the nocturnal melatonin peak (acrophase) at the same time as controls and significantly later than l-dopa/DCI treated patients (1:54 +/- 15.6 min [average clock time +/- SEM in minutes] vs. 1:45 +/- 15.6 min vs. 0:13 +/- 40.8 min). The amount of secreted melatonin did not differ among the three groups. Stage and duration of Parkinson's disease did not correlate with the amount of secreted melatonin. Patients of the tremor subgroup, however, secreted more melatonin than patients presenting only with rigidity and akinesia. The phase advance in Parkinson patients treated with l-dopa/DCI is possibly due to a central nervous dopaminergic effect elicited by l-dopa administration and not inherent to Parkinson's disease per se.

We studied the effects of L-threo-DOPS (L-DOPS) on the concentrations of total (conjugated and unconjugated) dopamine (DA) and norepinephrine (NE) in the cerebrospinal fluid (CSF) of parkinsonian patients with freezing phenomenon. The NE concentration increased remarkably and dose-dependently after administration of L-DOPS in both L-dopa/carbidopa-pretreated and untreated patients. The DA concentration also increased mildly but significantly in L-dopa/carbidopa-untreated patients. Freezing phenomenon improved in 6 out of 8 patients at Hoehn and Yahr's stage III, and 1 out of 5 patients at stage IV. These results indicate that L-DOPS administration increases the NE concentration dose-dependently, and is effective for freezing of gait of moderate severity.

We have quantified by receptor autoradiography the number of NK1 receptors, using [125I] Bolton-Hunter labeled substance P, in striatum and pallidum (internal (GPi) or external (GPe) segment) of patients suffering from Alzheimer's (AD) and Parkinson's disease (PD). When compared to non-neurologic controls, a significant increase in the number of NK1 sites has been observed in the striatum of PD patients. No significant differences were observed for the GPi and GPe. We observed no significant differences from controls in the number of NK1 sites in the striatum and pallidum of AD cases. However, the number of NK1 sites in the striatum of AD patients was significantly lower than that of PD patients. These results show that the expression of NK1 receptors in the basal ganglia is affected in PD.

A double-blind, cross-over trial with 12 patients with Alzheimer's disease (AD) was carried out primarily to test the suitability of this design in the investigation of the clinical effects of selegiline (10 mg/day) in AD. Cerebrospinal fluid (CSF) samples for the determination of concentrations of noradrenaline (NA) and several monoamine metabolites were collected at baseline and at the end of both four-week treatment periods (placebo and selegiline). The severity of dementia was assessed using Ferm's and Gottfries-Bråne-Steen (GBS) dementia scales. The concentrations of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the NA metabolites, 3,4-dihydroxyphenylglycol (DHPG), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) decreased significantly during selegiline treatment. There was a clear trend of reduction in concentrations of homovanillic acid (HVA) during selegiline treatment, whereas the concentrations of NA, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan did not differ significantly. The study design was not suitable for the analysis of the clinical results as there was a significant carry-over effect in both scales. As only the first period data could be used in the analysis, there were no significant differences in the scores of Ferm's or GBS scales, but clear positive trends could be detected in favour of selegiline.

We studied age-related changes in the concentrations of monoamines, amino acids, and their related substances in the cerebrospinal fluid on 144 neurologically normal subjects. The concentrations of tyrosine, 3-O-methyldopa, dopamine (total), norepinephrine (total), homovanillic acid, p-hydroxyphenylacetic acid, and 5-hydroxytryptophan increased significantly with age (p < 0.05), and the concentration of 3.4-dihydroxyphenylacetic acid displayed a non-significant trend to decrease, whereas concentrations of other monoamine precursors and metabolites were unchanged. We found the significant positive correlations between the concentrations of HVA and 5-HIAA (p < 0.001), between tyrosine and tryptophan (p < 0.001), and between tyrosine and 3-O-methyldopa (p < 0.001). The concentrations of asparagine, glycine, taurine, and alanine increased significantly with age (p < 0.05), while glutamine, arginine, and threonine concentrations did not change with age. The aspartate, glutamate, and GABA concentrations displayed the non-significant trends to decrease in the elderly subjects. The concentrations of aspartate, glutamate, and GABA had mutually significant positive correlations (p < 0.05), but had significant negative correlations with the concentrations of some neutral amino acids. The urate and xanthine concentrations increased significantly with age (p < 0.01). These findings suggest that the concentrations of monoamine and amino acid transmitters and their related compounds in the cerebrospinal fluid reflect age-related changes in the synthesis, release, and reuptake mechanisms of the transmitters and their transport mechanisms across the blood-brain barrier.

After acid gel-chromatography cerebrospinal fluid and serum levels of immunoreactive insulin-like growth factor 1 and 2 (IGF-1 and IGF-2) were determined in patients with dementia of the Alzheimer type (AD) and in healthy subjects. The AD CSF levels of immunoreactive IGF-1 did not differ from the subjects but the levels of immunoreactive IGF-2 was significantly elevated in both serum and CSF in the AD patient group. Additionally immunoreactive IGF-1 in AD serum was found to be significantly elevated. To characterize the CSF IGF binding protein activity (IGFBP), ligand blotting was performed on whole CSF from AD patients and subjects. The results demonstrate two major forms of IGFBP in CSF with approximate molecular weights of 33 KDa and 30 KDa. The two IGFBP forms are suggested to represent IGFBP-2 and IGFBP-6. A highly significant increase in both the IGFBPs was observed in the CSF of the AD patients compared to the healthy subjects.

A course of treatments with electroconvulsive shock (ECS) has been reported to reestablish L-dopa efficacy in patients with advanced Parkinson's disease. We wished to determine if ECS could modify L-dopa and dopamine metabolism in an animal model of Parkinson's disease. Therefore, we administered repeated ECS (8 ECS at 48 hr intervals) to rats with partial destruction of the nigrostriatal dopamine pathway and used the cerebral microdialysis technique to monitor extracellular concentrations of dopamine and dopamine metabolites (DOPAC and HVA) in the corpus striatum. The control group of animals received sham-ECS treatments. Basal dopamine levels were decreased by 20% in animals receiving repeated-ECS versus sham-ECS. DOPAC levels, on the other hand, were increased by 84% in animals receiving repeated-ECS. HVA levels were equal in the two groups. Following L-dopa administration, dopamine and HVA levels increased equally in control animals and animals which had previously received repeated-ECS. DOPAC concentrations were uniformly greater in rats receiving repeated-ECS. When ECS was administered acutely, dopamine levels increased 390% and returned to baseline values in 75 minutes, DOPAC and HVA were unchanged, and 5HIAA levels decreased 30%. We conclude that 1) acute ECS administration produces a transient, marked release of striatal dopamine and 2) repeated ECS can reset the level of basal dopamine release, a finding compatible with ECS-induced dopamine receptor supersensitivity, and 3) neither single nor repeated administration of ECS has a major effect on the formation of dopamine or HVA from exogenously administered L-dopa although there was a strong tendency for increased DOPAC formation. ECS may exert its putative antiparkinsonian effect by enhancing dopamine receptor sensitivity.

An anthropometric study was performed in 95 subjects (53 male, 42 female) with Parkinson's disease. Weight, height, triceps and biceps skin-fold thicknesses, and mid-arm circumference were recorded. A high incidence of undernutrition was found (23.6% of males and 22.5% of females, as defined by recent British guidelines). A subgroup of severely disabled patients with Parkinson's disease had a significantly lower mean body mass index than a similarly disabled control group with chronic pyramidal upper motor neuron lesions (males 20.6 v 23.2 kg/m2 p < 0.05; females 20.6 v 26.6 kg/m2 p < 0.01), suggesting that the undernutrition is not due to chronic illness or immobility alone. Correlation between anthropometric indices and clinical features of disease demonstrated that the presence of moderate or severe dyskinetic movements was the clinical parameter most strongly related to undernutrition. The reduction in anthropometric indices was most marked for skin fold thickness (related to percentage body fat) and least for arm muscle circumference (related to lean body mass); therefore the weight loss seen in Parkinson's disease is primarily due to fat loss rather than muscle loss.