Decrease in human striatal dopamine D2 receptor density with age: a PET study with [11C]raclopride.

The effect of age on human striatal dopamine D2 receptors was investigated with positron emission tomography (PET) using [11C]raclopride as a radioligand. Twenty-one healthy volunteers aged from 20 to 81 years were studied. An equilibrium method was applied and two separate PET scans with different specific activities of [11C]raclopride were performed. The maximal number of receptors (Bmax) and their dissociation constant (Kd) were calculated using Scatchard analysis. There was an age-dependent decline in the Bmax (r = -0.49; p = 0.02) of striatal D2 receptors while the Kd remained unchanged. The results show that there is an age-related loss of striatal D2 receptors, which, together with other changes in the brain nigrostriatal dopaminergic system, may contribute to extrapyramidal symptoms associated with aging.

Function of dopamine receptors in Parkinson's disease: prolactin responses.

In 64 patients with Parkinson's disease (PD), the basal level of prolactin (PRL) was normal. Bromocriptine (BCT) caused a significant suppression of PRL in all parkinsonian patients and controls. When given after BCT treatment, thyrotropin-releasing hormone (TRH) induced a significantly lower PRL rise in recent-onset parkinsonian patients than in controls or advanced patients. In advanced parkinsonian patients with daily fluctuations in disability, the corresponding TRH-induced PRL response was significantly higher than in controls. In advanced parkinsonian patients without fluctuations, the PRL response to TRH was almost the same as in controls.

[18F]-6-fluorodopa PET scanning in Parkinson's disease after selective COMT inhibition with nitecapone (OR-462).

PET studies were performed to investigate the effects of a new cathechol-O-methyltransferase (COMT) inhibitor, nitecapone (OR-462 [3-(3,4-dihydroxy-5-nitrobenzylidene)- 2,4-pentadione]), on the accumulation of dopamine in the striatum and whether it is able to improve [18F]6-fluorodopa imaging of the brain. Altogether, three patients with Parkinson's disease (PD) and three normal volunteers were examined, first without nitecapone and then with an oral dose of 100 mg of nitecapone 1 hour before the IV injection of 3 mCi of [18F]6-fluorodopa. High-pressure liquid chromatography analysis of arterial plasma samples showed a significant reduction in the metabolic conversion rate from [18F]6-fluorodopa to [18F]3-O-methylfluorodopa after the administration of nitecapone. PET studies showed that nitecapone significantly (p less than 0.05) increased the [18F]6-fluorodopa accumulation in the striatum both in PD patients and normal controls; the magnitude of this increase was 20.0 +/- 5.5% (mean +/- SEM). The ratio of radioactivity in the striatum and arterial plasma was increased 39.0 +/- 5.0% (mean +/- SEM) after the administration of nitecapone. Consequently, the quality of PET images after OR-462 was better, which has implications for future [18F]6-fluorodopa studies. In addition, COMT inhibition may have clinical advantages by improving levodopa treatment in PD.

Positron emission tomography study of human narcolepsy: no increase in striatal dopamine D2 receptors.

We investigated dopamine D2 receptors in the caudate nucleus and putamen with positron emission tomography in seven patients with narcolepsy and seven healthy controls by using [11C]raclopride as a ligand. We applied an equilibrium method and Scatchard principle to give a quantitative estimation of the number (Bmax) and dissociation constant (Kd) of the receptors. Both the Bmax and Kd were within the normal range in the caudate nucleus and putamen in narcoleptic patients. We found no evidence for increased D2 receptor binding in narcolepsy.

PET studies on brain monoamine transporters with carbon-11-beta-CIT in Parkinson's disease.

UNLABELLED: The cocaine analog 2 beta-carbomethoxy-3 beta-[4-iodophenyl]tropane (beta-CIT) labeled with 11C was used to study dopamine reuptake sites with PET. METHODS: Three normal subjects and nine patients with Parkinson's disease were investigated. Each of them underwent a dynamic PET scan (25 timeframes over 80 min) with [11C]-beta-CIT. A dose of 102.5-211.3 MBq (2.77-5.71 mCi) of this ligand was administered intravenously and a PET examination with an ECAT 931/08 PET camera was carried out. Ratios between the striatal/cortical/thalamic/midbrain and cerebellar uptake of this radioligand were calculated. RESULTS: The highest accumulation of [11C]beta-CIT was observed in the caudate and putamen, though there was some uptake in the thalamus and the midbrain. Cortical uptake was negligible. Carbon-11-beta-CIT accumulated significantly less in the putamen of the Parkinson's patients than in the normal subjects. The putamen-to-cerebellum ratio in the Parkinson's patients was 1.59 +/- 0.04 and 1.80 +/- 0.13s (p = 0.028) in the normal subjects. In the caudate, there was no significant difference between the Parkinson's patients and the normal subjects. CONCLUSION: These results imply that [11C]beta-CIT is a useful compound for carrying out a PET examination of the function of the presynaptic monoaminergic neurons both in normal and pathological brains.

PET studies on dopamine D1 receptors in the human brain with carbon-11-SCH 39166 and carbon-11-NNC 756.

UNLABELLED: PET studies were carried out on brain dopamine D1 receptors using two new ligands, [11C]SCH 39166 and [11C]NNC 756. METHODS: Four normal subjects and eight predominantly unilateral patients with early Parkinson's disease were investigated. Each of them underwent both a PET scan with [11C]SCH 39166 and one with [11C]NNC 756. A dose of about 185 MBq (5 mCi) of these ligands was administered intravenously and a dynamic PET scan with an ECAT 931/08 PET camera was carried out. Ratios between the striatal and cerebellar uptake of these compounds were calculated. RESULTS: Both [11C]SCH 39166 and [11C]NNC 756 accumulated in the striatum. There was also some neocortical binding; 75% of the striatal value in the case of [11C]SCH 39166 and 60% with [11C]NNC 756 which displayed higher (p < 0.01) uptake in the striatum than [11C]SCH 39166. There were no significant side-to-side differences in the controls nor in the parkinsonian patients. CONCLUSIONS: These results imply that both [11C]SCH 39166 and [11C]NNC 756 can be used in PET studies for the visualization and quantification of dopamine D1 receptors. Since [11C]NNC 756 has a significantly better signal-to-noise ratio in the striatum than [11C]SCH 39166, it seems to offer definite advantages for studies of D1 receptors.

PET studies on the memory processing of word pairs in bilingual Finnish-English subjects.

This study examined the fundamental question whether verbal memory processing in two unrelated languages is mediated by a common neural system or by distinct cortical areas. Ten right-handed, male Finnish--English adult late bilinguals who had acquired the second language after the age of 10 were scanned whilst either encoding/retrieving word pairs in their mother tongue (Finnish) or in a foreign language (English). Within each language, subjects had to encode and retrieve four sets of 12 visually presented paired word associates which were not semantically related. Two sets consisted of highly imageable words (e.g. monkey-table; koira-lasi) and the other two sets of abstract word pairs (e.g. freedom-moral; uhka-suure). Presentation of pseudowords served as a reference condition. An emission scan was recorded after each intravenous administration of O-15 water. Encoding was associated with prefrontal and hippocampal activation. During memory retrieval, precuneus showed a consistent activation in both languages and for both highly imageable and abstract words. Although the brain mechanisms of the two languages share common components, differential activations were found in Broca's area and in the cerebellum as well as in the angular/supramarginal gyri according to the language used.

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.

Risk for Parkinson's disease: twin studies for the detection of asymptomatic subjects using [18F]6-fluorodopa PET.

Positron emission tomography (PET) studies were carried out with [18F]6-fluorodopa ([18F]6-FD) in monozygotic (MZ) and dizygotic (DZ) twins for the clarification of dopaminergic function. Four MZ and four DZ pairs of twins, each pair consisting of a parkinsonian index case and an asymptomatic co-twin, were collected from the Nationwide Twin Cohort. The control group comprised 14 healthy volunteers. [18F]6-FD PET examinations with a Siemens/CTI 931/08 scanner were performed dynamically over 90 min. The regions-of-interest analysis included the caudate, the putamen and the occipital reference regions. Patlak plots were calculated using occipital tissue input function. The accumulation of [18F]6-FD in the putamen of the asymptomatic co-twins was significantly lower than that in the normal subjects. This result implies that there may be a preclinical stage of Parkinson's disease in the apparently normal co-twins at the time of the PET study.

Positron emission tomography shows that impaired frontal lobe functioning in Parkinson's disease is related to dopaminergic hypofunction in the caudate nucleus.

We examined the relation between the dopaminergic function and the cognitive performance of patients with Parkinson's disease (PD). The subject sample consisted of ten patients in the early course of PD and with no previous antiparkinsonian medication. The dopaminergic function of the caudate nucleus and the putamen was studied with [(18)F]fluorodopa positron emission tomography, and the cognitive performance with a comprehensive battery of neuropsychological tests including tests sensitive to frontal lobe function. The decreased [(18)F]fluorodopa uptake in the right caudate nucleus was found to be related to slow processing time, measured as the difference between the incongruent and the congruent subtests of the Stroop Test (r=-0.85, P=0.002), a similar trend was seen in the left caudate (r=-0.60, P=0.07). Similar correlation was not detected in the putamen. The present findings provide evidence that the decreased dopaminergic function in the right caudate nucleus is related to the impaired performance in tests sensitive to frontal lobe function in patients at an early stage of PD and with no antiparkinsonian medication.

Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson's disease: a PET study with [11C]raclopride.

Striatal dopamine D2 receptors were studied, using positron emission tomography (PET), in 10 patients with early Parkinson's disease without any antiparkinsonian medication and in 14 healthy controls. [11C]Raclopride was used as ligand and an equilibrium method was applied. The maximum count of receptors (Bmax) and their dissociation constant (Kd) were calculated according to the Scatchard principle. In parkinsonian patients, the Bmax of D2 receptors was increased in the putamen contralateral to the predominant symptoms, as compared to the opposite putamen, by 33% (p = 0.0008). In the caudate nucleus no significant side to side differences was noted. On comparison with age-matched healthy controls, Bmax values in the putamen (p = 0.0012) but not in the caudate nucleus contralateral to the side of predominant clinical symptoms were increased in PD patients. The Kd values were unchanged. The difference in putaminal Bmax values between the opposite hemispheres correlated with the difference in the severity of parkinsonian motor symptoms between the two body sides (r = 0.69, p = 0.03). The present results show that there is both a relative and absolute increase in the number of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early 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.

Brain substance P receptors in Parkinson's disease.

The distribution of SP receptors was studied both in the normal human brain and in the parkinsonian brain by means of tritiated SP. The highest levels of binding were found in the striatal areas and in the NbM. The distribution was similar to that found in laboratory animals in earlier studies. In PD the binding was significantly reduced in the NbM and parietal cortex as compared with controls. The level of SPLI was reduced in both parts of the SN, in the NbM, and in the GPi.

Assessment of psychiatric and psychosocial factors disposing to chronic outcome of dermatoses.

In many skin diseases, itching and scratching is a vicious circle, which prolongs the disease. The aim of this study was to investigate the mechanisms which make itching skin diseases more chronic. The patients consisted of seven diagnostic groups--79 inpatients all together. The dermatoses were: dermatitis herpetiformis, lichen ruber planus, chronic eczema, atopic eczema, neurodermatitis circumscriptus, prurico psychogenous and lichen obtusus corneus. Both psychiatric and dermatological examinations were performed. Psychiatric disturbance was clearly greater than in the average population. The chronifying mechanisms were the following: personality disorder as a treatment problem; emotional infantility, which makes the illness itself an important security factor; itching and scratching as pleasure and content of life; the accumulation of various other diseases, both somatic and psychiatric; and untreated depression. Information was obtained on the possibilities of psychiatric treatment and psychosocial rehabilitation.

Psychosomatic aspects in dermatoses.

The purpose of this presentation is to offer a classification of psychocutaneous disease and to examinine factors which result in itching and scratching becoming chronic. Pruritus is a very common sensation in dermatoses. All forms of itching, whatever the cause, may be intensified by emotional stress. The patient sample of my own study consisted of seven diagnostic groups, giving a total of 99 patients. The dermatoses were: dermatitis herpetiformis, lichen ruber planus, chronic eczema, atopic eczema, neurodermatitis circumscripta, lichen corneus obtusus and pruritus psychogenes. The principal findings were as follows: 1. Many of the different mechanisms by which skin diseases became chronic had a psychological background. 2. Psychiatric disturbances were clearly more common than in the average population. Possibilities of psychiatric treatment were evaluated. The results confirm the hypothesis that in those skin diseases in which the disease mechanism is not yet sufficiently understood, psychosomatics is of considerable importance or offers an easier way to explain the mechanism.

The relationship between cortical recruiting responses and ponto-geniculo-occipital waves during paradoxical sleep in the cat.

In an earlier study it was found that during paradoxical sleep (PS) thalamo-cortical recruiting responses (RRs) and rapid eye movements usually did not appear simultaneously. As shown elsewhere, ponto-geniculo-occipital (PGO) wave activity and rapid eye movements are during PS closely related to each other in time. Similarly, in the present study it was observed that during paradoxical sleep in cats in which the center median nucleus of the thalamus was being stimulated at a rate of 7--9 Hz PGO waves in the geniculate nuclei did not in the rule occur in the presence of RRs recorded from the motor cortex. This effect was most pronounced with respect to series of PGO waves which usually occur at a rate of 4--7 Hz. On the basis of these experiments it was concluded that PGO waves and RRs are reciprocal events and mutually exclusive. Considering to the well-known fact that RRs represent synchronization, this negative correlation between RRs and PGO waves indicates that the desynchronizing tendency typical to paradoxical sleep is most pronounced during the occurrence of PGO waves.

Pontine gigantocellular field neuron activity time-locked with the PGO waves in the transitional phase of sleep in the cat.

The extracellularly recorded discharge of pontine gigantocellular tegmental field (FTG) neurons was studied in the cat during the transitional phase of sleep (TPS), which signifies in this study the shift from slow wave sleep (S) to paradoxical sleep (PS). The first appearance of pontogeniculo-occipital (PGO) waves, which were led off from the lateral geniculate nucleus, indicated the start, and the decrease of neck muscle tone the end of TPS. TPS was chosen because most PGO waves were then isolated and thus suitable for comparison with the discharge of neurons, which were localized to the antero-lateral part of the FTG. In order to analyze the possible role of these neurons in the control of PGO wave activity, the mean discharge rate of FTG neurons was studied in greater detail during 200 ms periods before and after the onset of each isolated PGO wave. Most FTG neurons discharged phasically and their activity was closely related to isolated PGO waves, so that the highest rate of unit discharge occurred within 40 ms period after the onset of the isolated PGO wave, being time-locked with its first deflection.

Sleep movements and associated autonomic nervous activities in patients with Parkinson's disease.

Nine parkinsonian patients were studied during one night using the static charge sensitive bed (SCSB) method for the monitoring of respiration, ballistocardiogram (BCG) and body movements. The parkinsonian sleep was more restless than that of the controls. As the SCSB-defined levels of autonomic nervous activity were concerned, the amount of motor active wakefulness (MAW) was significantly (P less than 0.05) increased in parkinsonian patients, who also had less quiet sleep (P less than 0.05) than the controls. Parkinsonian tremor was present during 29.8 +/- 15.8% of the time in bed. Usually it was observed during wakefulness; it disappeared when the patient fell asleep. The frequency of turning-over events in bed was smaller in the parkinsonian patients than in the controls (P less than 0.05). When the heart rate changes associated with sleep movements were studied it was found that the parasympathetic deceleration component in the parkinsonian patients was absent. The motor dysfunction associated with Parkinson's disease is reflected in many ways in the sleep movement activity. Sleep disturbances in PD seem to be secondary in character; i.e. they can be due to impaired motor functions like turning around in the bed, or due to impaired arousal mechanisms during sleep.