Choline acetytransferase activity and striatal dopamine receptors in Parkinson's disease in relation to cognitive impairment.

Brain tissue from 44 patients with Parkinson's disease (PD) and 36 age-matched controls was examined for choline acetyltransferase (ChAT) activity, and for densities of D1 and D2 dopamine receptors. Brain samples were examined for Alzheimer' disease (AD) type changes and for Lewy bodies (LBs), and for apolipoprotein E genotype. Patients were evaluated for the stage of cognitive impairment using Reisberg's global deterioration scale. ChAT activity in PD was reduced in all brain areas examined, being 51% of the control mean in the hippocampus (P<0.001), 57% in the prefrontal cortex (P< 0.001) and 64% in the temporal cortex (P<0.001). The number of LBs had a significant negative correlation with ChAT activity in both prefrontal (r=-0.33, P<0.05) and temporal cortex (r=-0.32, P<0.05). The reduction in ChAT activity in the prefrontal cortex had a significant negative correlation (r=-0.38, P=0.012) with the extent of cognitive impairment. When the CERAD class 'C' was excluded, cognitive impairment correlated significantly with both prefrontal ChAT activity (r=-0.52, P=0.0051) and the density of D1 dopamine receptors in the caudate nucleus (r=-0.40, P=0.037). The number of D1 and D2 dopamine receptors was reduced in both caudate nucleus and putamen in PD patients without neuroleptics as compared to controls. An increased D2 receptor number was found in the caudate nucleus and putamen in PD patients treated with neuroleptics. The present study showed that cognitive decline in PD is associated with reduced ChAT activity in the prefrontal cortex and the D1 dopamine receptor number in the caudate nucleus, even in the absence of AD-type pathology.

Human brain methionine- and leucine-enkephalins and their receptors during ageing.

Brain Met- and Leu-enk levels were investigated with radioimmunoassay and their binding to enkephalin receptors was studied with [3H]Met- and [3H]Leu-enkephalin in 56 human subjects (4-93 yr). Of the brain areas investigated, the head of the caudate nucleus and pallidum showed an age-associated decline for both Met- and Leu-enk content. In the substantia nigra and in putamen, no significant age-effect was seen. Binding of the enkephalins, which was studied in the head of the caudate nucleus and hippocampus, did not show significant age dependency. In conclusion, ageing affects human brain enkephalin levels but not their receptor binding, at least in brain areas investigated in the present study.

Brain methionine- and leucine-enkephalin receptors in patients with dementia.

Brain [3H]Met- and [3H]Leu-enkephalin binding was studied in patients with Alzheimer's disease (AD) and vascular dementia (VD), and in age-matched controls. Brain areas investigated were the internal and external globus pallidus, amygdala, hippocampus and temporal cortex. In AD, the binding of both enkephalins decreased in all brain areas examined, except in the external globus pallidus for both enkephalins and in the internal globus pallidus for leucine-enkephalin. Scatchard analysis of amygdaloid samples showed a decrease in the number of receptors (Bmax) without any change in their affinity (Kd). In patients with VD, no significant changes in enkephalin binding were seen. Thus, in AD, enkephalin binding (mainly reflecting delta opioid receptor subtype) is decreased, especially in limbic areas.

Decreased raphe serotonin in rabbits with experimental herpes simplex encephalitis.

Increased monoamine metabolism in experimental herpes simplex virus (HSV) encephalitis is well established. Both serotonin (5-HT) and dopamine (DA) systems are affected. HSV invades the raphe nuclei after its entry into the brain stem. However, no studies have been published concerning influences of HSV on the neurotransmitters in the raphe. In the present study, concentrations of 5-HT and DA and their metabolites in the raphe nuclei and related brain regions in rabbits with fulminant HSV encephalitis have been analyzed using high-pressure liquid chromatography. Encephalitis was induced by corneal inoculation with HSV. Homovanillic acid (HVA) and dihydroxyphenyl acetic acid (DOPAC) concentrations and HVA/DA ratios were increased in the raphe nuclei suggesting increased DA turnover. The most substantial changes were bilaterally decreased 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the raphe nuclei. The decrease in the raphe 5-HT was reflected also to the projection areas in the hemispheres, where 5-HT concentrations were lower in HSV-inoculated rabbits than in controls. The changes strongly suggest a direct influence of HSV on serotoninergic neurons. Since the ventral parts of the limbic system have rich serotoninergic afferents from the raphe, this also suggests that HSV may reach hemispheres in HSV encephalitis from the brain stem via the ascending serotoninergic system.

A post-mortem study on striatal dopamine receptors in Parkinson's disease.

Striatal dopamine D1 and D2 receptors were investigated in 49 patients with Parkinson's disease (PD) and 33 age-matched controls with [3H]SCH 23390 and [3H]spiroperidol as ligands respectively. A full Scatchard analysis giving Bmax and Kd values was performed. In the caudate nucleus, a small but significant decrease in the number of D1 and D2 receptors was seen, whereas in the putamen the number of dopamine receptors was unchanged. Treatment with neuroleptics was found to increase the number of D2 receptors both in the caudate nucleus and putamen. The number of neither D1 nor D2 receptors correlated neither with the duration of disease or levodopa treatment of the patients nor with the post-mortem delay or storage time of the samples. Furthermore, no association was found between either D1 or D2 receptor number and clinical variables of the patients. The activity of choline acetyltransferase (ChAT) was found to be unchanged in the striatum, whereas a marked decline was seen in the hippocampus and cortical areas, indicating that intrinsic striatal cholinergic neurons are not affected in PD. The present results suggest that there is a modest decline in the number of striatal dopamine D2 receptors in advanced patients with PD at the end stage of the disease.

A postmortem study of brain nicotinic receptors in Parkinson's and Alzheimer's disease.

Brain nicotinic receptors were studied in the frontal cortex, temporal cortex, hippocampus and caudate nucleus in patients with Parkinson's disease (PD), Alzheimer's disease (AD) and control. The Bmax and Kd values of (-)-[3H]nicotine binding were determined with a Scatchard analysis. The number of nicotinic receptors declined both in PD and in AD patients in all brain areas examined. The Kd values were unchanged. There was a negative correlation between the degree of dementia in PD patients and the number of nicotinic receptors in the frontal cortex. A similar correlation was seen between the muscarinic/nicotinic receptor ratio in the frontal cortex and the degree of dementia in PD patients. The present findings indicate that nicotinic receptors are affected not only in AD, but also in PD and that dysfunction of the cholinergic system in the frontal cortex is involved in the dementia process in PD.

Age-dependent decline in human brain dopamine D1 and D2 receptors.

Dopamine D1 and D2 receptor binding was investigated in the caudate nucleus and putamen in 65 individuals ranging from 6 to 93 years of age. [3H]SCH 23390 and [3H]spiroperidol were used as ligands for D1 and D2 receptors, respectively. A full Scatchard analysis with several ligand concentrations was performed yielding Bmax and Kd values. The number of D1 and D2 receptors declined with age both in the caudate nucleus and putamen without any change in the mean dissociation constant. The ratio of D1:D2 receptors remained unchanged. The results show that the dopaminergic system degenerates in the aging striatum and may contribute to the frequent occurrence of extrapyramidal symptoms in the elderly.

Brain muscarinic receptor subtypes are differently affected in Alzheimer's disease and Parkinson's disease.

The muscarinic receptor subtypes determined by displacing [3H]quinuclidinyl benzylate by carbachol showed distinct profiles in Alzheimer's disease (AD) and in Parkinson's disease (PD). A decrease in the M2-receptor count was seen in the hippocampus in AD as compared to controls, while PD patients had unaltered binding. By contrast, PD patients had increased M2-binding in the frontal and temporal cortex, whereas unchanged binding was seen in AD. In PD the total number of cortical muscarinic receptors was negatively associated with the activity of ChAT, but had a positive correlation with the degree of dementia of the patients.

Dopamine D-1 receptors in the parkinsonian brain.

Dopamine D-1 receptors were analyzed in the caudate nucleus, putamen, pallidum, substantia nigra and nucleus accumbens in 20 patients with Parkinson's disease and in 18 age-matched controls by the binding of [3H]flupenthixol. The binding was decreased in the substantia nigra in those parkinsonian patients who were not treated with levodopa. A significantly increased number of D-1 receptors was found in the putamen of patients with Parkinson's disease, especially in those who were treated with levodopa. The increased binding of [3H]flupenthixol was most prominent in those six parkinsonian patients who still had therapeutic response to levodopa. In addition, orofacial dyskinesias were seen in three of these patients. The results of this study indicate that there may be denervation supersensitivity of striatal neurons and also a loss of striatonigral neurons in Parkinson's disease.

Brain muscarinic receptors in senile dementia.

Muscarinic receptors were analyzed in various post-mortem brain samples of 39 patients with different types of dementia and of 30 age-matched controls by the specific binding of [3H]QNB. The diagnoses were verified neuropathologically. The binding of [3H]QNB was significantly decreased in the hippocampus, amygdala and nucleus accumbens in patients with Alzheimer's disease (AD) and with combined type of dementia (CD), whereas in patients with multi-infarct dementia (MID) the binding was not significantly decreased in the limbic areas but only in the caudate nucleus. Of the clinical variables, orofacial dyskinesias in patients with AD but not with MID correlated with low brain weight and with the decreased [3H]QNB binding in the striatum and frontal cortex. The results reveal some differences between AD and MID. Changes in muscarinic receptor binding show that the cholinergic neurons in the limbic system are especially vulnerable in patients with AD and CD.

Brain neurotransmitters and neuropeptides in Parkinson's disease.

Parkinson's disease is characterized by a deficiency of dopamine in the nigrostriatal system. However, changes in dopamine neurons were found also outside the extrapyramidal system, showing that there is a more general brain defect than just the loss of substantia nigra dopamine neurons. With regard to the behavior of striatal D-2 receptors it was possible to divide parkinsonian patients into two subgroups, because either a decrease or an increase in the number of D-2 receptors was found. Clinically, the patients with a decreased number of striatal D-2 receptors were more disabled and had lost the beneficial response to levodopa. D-3 receptor binding sites were decreased in the parkinsonian striatum. Changes in the cholinergic-muscarinic receptors in the striatum seem to be related to changes in D-2 receptors, and muscarinic receptor supersensitivity was found in cortical areas. GABA receptor binding was decreased in the substantia nigra. In the parkinsonian brain there seems to be supersensitivity of a population of enkephalin receptors (delta) in the striatum and in the limbic system and also a loss of others (mu) in the striatum. Furthermore, the Met-enkephalin content was decreased in the parkinsonian substantia nigra. A decreased concentration of substance P was found in the substantia nigra of all parkinsonian patients and in the putamen of those patients who had not received levodopa treatment. The somatostatin level was decreased in the frontal cortex in relation to dementia. There are thus multiple neuronal disturbances in the parkinsonian brain, although those of the nigrostriatal dopamine neurons seem to be the greatest and are more closely related to parkinsonian clinical features and to treatment responses.

Brain enkephalin receptors in Parkinson's disease.

Brain enkephalin receptors were studied in post-mortem brain samples of 27 patients with Parkinson's disease and of 26 control subjects without extrapyramidal disorders by the radioligand-binding technique using 3H-leu-enkephalin, 3H-met-enkephalin and 3H-naloxone. The specific binding of both 3H-leu- and 3H-met-enkephalins was significantly increased in the caudate nucleus, putamen, nucleus accumbens, limbic cortex and hippocampus. Scatchard analysis showed that there was an increase in the receptor number, but no significant changes in the mean dissociation constant. Levodopa treatment did not have any significant effect on the enkephalin bindings. A significantly decreased binding of 3H-naloxone was found in the parkinsonian caudate nucleus. Thus there is a supersensitivity of a population of enkephalin receptors in the striatum and limbic system, as well as a loss of other opiate receptors in the striatum, suggesting the involvement of certain brain enkephalin neurons in the pathophysiological process of Parkinson's disease.

Brain receptor changes in Parkinson's disease in relation to the disease process and treatment.

With regard to the behaviour of striatal D-2 receptors it was possible to divide parkinsonian patients into two subgroups, because either an increase or a decrease in the number of D-2 receptors was found. Dyskinesias, daily fluctuations in performance, and psychotic episodes together with neuroleptic medication, were associated with an increase in the number of striatal D-2 receptors. Clinically, the patients with a decreased number of striatal D-2 receptors were more disabled and had lost the beneficial response to levodopa. In agreement with post-mortem brain studies, increased responses of prolactin secretion to TRH in vivo also suggested a decreased D-2 receptor function in parkinsonian patients with recent onset and supersensitivity in patients with on-off phenomena. D-3 receptor binding sites had decreased in the parkinsonian striatum. In contrast to D-2 receptors, the D-3 sites seem to be less sensitive to treatment with neuroleptic drugs. Changes in the binding of 3H-enkephalins indicated that there is a supersensitivity of a population of enkephalin receptors (delta) in the striatum and limbic system. Treatment with levodopa did not have any significant effect on the binding of 3H-enkephalins. The binding of 3H-naloxone decreased in the parkinsonian caudate nucleus, suggesting that a population of opiate receptors (mu) is located on the dopamine nerve terminals in the striatum. Thus there are multiple neuronal disturbances in the parkinsonian brain, although those of nigrostriatal dopamine neurons seem to be greater and more closely related to the parkinsonian clinical features and to treatment responses.

Dopamine receptors in the Parkinsonian brain.

Striatal dopamine receptors were studied in 44 patients with Parkinson disease by the radioligand-binding technique using 3H-spiroperidol. The specific binding of 3H-spiroperidol was either significantly increased or reduced in the caudate nucleus and putamen of parkinsonian patients without levodopa therapy. Scatchard analysis showed that there were corresponding changes in the receptor number, but no significant changes in the mean dissociation constant. The increased binding of 3H-spiroperidol in the basal ganglia was also found in parkinsonian patients suffering from psychotic episodes and treated with neuroleptic drugs. Normal and low binding of 3H-spiroperidol was found in patients treated with levodopa. Clinically, the patients with low binding were more disabled and had lost the beneficial response to levodopa. Thus in Parkinson disease in some patients a denervation supersensitivity seemed to develop and in some others a loss of postsynaptic dopamine receptor sites in the neostriatum. The latter alteration may contribute to the decreased response of parkinsonian patients to chronic levodopa therapy.