Ivo Podreka

SPECT imaging of dopamine and serotonin transporters with [123I]β-CIT. Binding kinetics in the human brain

Single photon emission computerized tomography (SPECT) studies in non-human primates have previously shown that the cocaine derivative [123I]-2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane ([123I]β-CIT) labels dopamine transporters in the striatum and serotonin transporters in the hypothalamusmidbrain area. Here, we report on the regional kinetic uptake of [123I]β-CIT in the brain of 4 normal volunteers and 2 patients with Parkinsons disease. In healthy subjects striatal activity increased slowly to reach peak values at about 20 hours post injection. In the hypothalamus-midbrain area peak activities were observed at about 4 hours with a slow decrease thereafter. Low activity was observed in cortical and cerebellar areas. The striatal to cerebellar ratio was about 4 after 5 hours and 9 after 20 hours. In 2 patients with idiopathic Parkinsons disease striatal activity was markedly decreased while the activity in hypothalamus-midbrain areas was only mildly diminished. Uptake into cortical and cerebellar areas appeared to be unchanged in Parkinsons disease. Consequently, in Parkinsons disease the striatal to cerebellar ratio was decreased to values around 2.5 after 20 hours. These preliminary methodological studies suggest that [123I]β-CIT is a useful SPECT ligand for studying dopamine and possibly also serotonin transporters in the living human brain.

beta-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo.

The cocaine analogue 2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane (β-CIT) is a potent ligand for both dopamine- and serotonin uptake sites which in its123I labeled form can be used for single photon emission computerized tomography (SPECT). It was demonstrated previously by SPECT-studies in non-human primates that123I-β-CIT binds to dopamine transporters in the striatum and to serotonin transporters in hypothalamus and midbrain. The aim of the present study was to compare123I-β-CIT binding in the brain stem of normal controls and a group of subjects under treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram.123I-β-CIT- SPECT was performed in 12 depressed patients under 20 mg (n=5), 40 mg (n=6) and 60 mg (n=1) citalopram daily, in one untreated depressed patient and in 11 controls at regular time intervals up till 24 hours p.inj. A highly significant reduction of β-CIT binding was found in an area including mesial thalamus, hypothalamus, midbrain and pons in patients under citalopram compared to controls (44.1 ± 14.4 vs. 82.3 ± 18.6 cpms/mCi × kg body weight; specific binding 4 hrs p.inj.; p=0.0001). No differences were seen between the high and low dose group and no changes were found in the striatum.123I-β-CIT binding in the brain stem and striatum in one untreated depressed patient fell within the range of control values. To our knowledge this is the first report directly demonstrating the effect of a selective serotonin uptake inhibitor in the brain in humans in vivo. SPECT measurements of serotonin uptake sites in patients with depression and other psychiatric disorders might provide better insights into the pathophysiology of these disorders and into mechanisms of drug action.

Cerebral correlates of imagining colours, faces and a map—I. SPECT of regional cerebral blood flow

The distribution of regional cerebral blood flow (rCBF) was assessed by single photon emission computerized tomography (SPECT) in subjects during a resting state and during imagining either colours or faces or a route on a map. Twelve out of 30 subjects reported the spontaneous occurrence of mental visual images during the resting state. In these subjects flow in both orbitofrontal regions was higher than in those subjects who had not experienced spontaneous imagery. Voluntary imagery led to an increase of regional flow indices in basal temporal regions of both hemispheres and to a rightwards shift of global hemispheric asymmetry. The local changes were distinctly more marked with faces than with any of the other two stimuli. Imagining faces was also the only condition that led to an increase of activity in the left inferior occipital region which has been suggested by previous studies as being a crucial area for visual imagery. It is concluded that the observed differences of rCBF patterns between imagery conditions are related to the amount of information conveyed by the mental image. In contrast to the results of a companion study on DC-shifts accompanying imagery there was no effect of the visual versus spatial character of the images.

Receptor and Transporter Imaging Studies in Schizophrenia, Depression, Bulimia and Tourette's Disorder—Implications for Psychopharmacology-

Summary: Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourettes disorder. Striatal D2 and 5-HTIA receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naive or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D2 receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D2 receptor occupancy rates and antipsychotic efficacy has been found. The measurement of S-HTIA receptors in drug-naïve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HTIA receptor binding potential in schizophrenia. β-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age-and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [124I]/β-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the β-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourettes disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-naïve TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drugnaive TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments.

Postictal Psychosis in Temporal Lobe Epilepsy

Summary:  Purpose: Postictal psychosis is a well‐known complication, occurring especially in patients with temporal lobe epilepsy. It usually runs a benign course. The literature on this topic is sparse, and the underlying pathogenic mechanisms are not known.

IBZM SPECT imaging of striatal dopamine-2 receptors in psychotic patients treated with the novel antipsychotic substance quetiapine in comparison to clozapine and haloperidol.

Abstract We investigated the striatal dopamine-2 (D2) receptor occupancy caused by different antipsychotic substances in 18 psychotic patients (16 with schizophrenic and two with schizoaffective disorder according to DSM-IV) with single photon emission computed tomography (SPECT) using 123I-iodobenzamide (IBZM) as tracer substance. Four patients were treated with the novel antipsychotic compound quetiapine (300–700 mg/day), six with clozapine (300–600 mg/ day) and eight with haloperidol (10–20 mg/day). They were compared with eight healthy controls. Measurement of S/F ratios and consecutive calculation of D2 receptor occupancy revealed a significantly lower striatal D2 occupancy rate with quetiapine and clozapine in comparison to haloperidol. In correspondence with the low striatal D2 receptor occupancy rates and again in contrast to the haloperidol treatment group, there were no extrapyramidal motor side-effects (EPS) in the quetiapine and clozapine treatment groups. Therefore, the reported data support the position that quetiapine can be considered to be an atypical antipsychotic substance due to its relatively weak striatal D2 receptor blocking property and therefore its low propensity to induce EPS.

Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol – a 123I-IBZM SPECT study

Abstract The striatal D2 dopamine binding was studied in schizophrenic patients treated with the novel atypical antipsychotic drug sertindole (n = 10). Comparisons were obtained with haloperidol (n = 8), clozapine (n = 6), risperidone (n = 11) and untreated healthy controls (n = 8) of a dataset which has partly been reported previously. 123I-Iodobenzamide (IBZM) single photon emission computerized tomography (SPECT) was used for estimation of striatal dopamine D2 receptor binding. Sertindole-treated patients exhibited significantly (P < 0.001) lower levels of striatal D2 binding (BG/FC ratio:1.28) compared with those treated with haloperidol (BG/FC ratio:1.09) and risperidone (8 mg:1.18) but significantly (P < 0.005) higher levels compared with clozapine (BG/FC ratio:1.49). However, if patients were pretreated with a depot neuroleptic, significantly (P < 0.05) higher striatal D2 binding (BG/FC ratio:1.12) has been obtained. Since sertindole has been shown to exert distinct clinical efficacy for treatment of positive and negative symptoms, our data are indicative that antipsychotic efficacy is not associated with a high degree of striatal D2 receptor occupancy in schizophrenic patients.

Opioid Addiction Changes Cerebral Blood Flow Symmetry

Changes in regional cerebral blood flow (rCBF) due to long-term abuse of opioids such as heroin or morphine are not yet fully understood in humans. The goal of the present study was to investigate rCBF alterations in a large sample of long-term opioid addicts in comparison to healthy controls. We investigated 21 opioid-dependent subjects, who were currently abusing heroin or were enrolled in a methadone or morphine maintenance program, and 36 healthy controls with 99mTc-HMPAO single photon emission computed tomography. We found a decrease in rCBF in most regions of interest in patients in comparison to controls. Long-term opioid dependence seems to decrease prefrontal CBF in particular. A right-greater-than-left CBF asymmetry in healthy subjects was reversed in patients. This change in CBF symmetry could reflect the different emotional status of opioid-dependent patients. Our findings are in line with neuropsychological investigations indicating a correlation of mood states with lateralization of hemispheric activation patterns.

Contributions of occipital and temporal brain regions to visual and acoustic imagery—A spect study

Regional cerebral blood flow (rCBF) was assessed by means of HMPAO-SPECT in two experimental groups. In a control condition both groups listened to abstract words, in the experimental condition they heard five names of objects. One group was advised to form visual images of the objects, the other group was advised to form acoustic images of the sounds made by these objects. Post-experimental questionnaires revealed that most of the subjects in the acoustic imagery condition had had visual images in addition to the acoustic ones. Both imagery conditions lead to approximately equal increases of rCBF in the left inferior occipital region and in the left thalamus. Flow increases in both hippocampal regions and the right inferior and superior temporal regions were larger in the acoustic than in the visual imagery condition. It is concluded that only the activation of left inferior occipital and left thalamic regions can be interpreted as being related to modality-specific visual aspects of imagery.

HM-PAO-SPECT in persistent vegetative state after head injury : prognostic indicator of the likelihood of recovery?

Management of patients presenting with traumatic persistent vegetative state (PVS) calls for extensive resources. The ability to predict whether or not a patient is likely to recover is a critical issue. In 12 patients with PVS admitted consecutively for early rehabilitation after head injury, pattern of brain activity was measured by99mTc-hexamethyl-propylenamineoxime (99mTc-HM-PAO) brain SPECT (single photon emission computer tomography). All patients were re-investigated after a mean observation period of 3 years. A global reduction of cortical blood flow was a reliable predictor of poor longterm outcome, but the demonstration of only focal deficits did not reliably indicate a favourable outcome. Brain SPECT may help to improve outcome prediction in patients with traumatic PVS.