Dopamine transporter and D2-receptor density in late-onset alcoholism.

RATIONALE: Late onset type 1 alcoholism has been suggested to be associated with an underlying dopaminergic defect. Therefore, it is relevant to study both postsynaptic D2-receptor and presynaptic dopamine transporter (DAT) densities among alcoholics. OBJECTIVE: We investigated DAT densities, along with striatal and extrastriatal dopamine D2-receptor densities, in nine nonviolent late-onset male alcoholics, who had no major mental disorder nor antisocial personality disorder (ASPD), and nine healthy controls. METHODS: [123I]PE2I and [123I]epidepride were used in SPECT imaging. RESULTS: DAT occupancy ratios (striatum/cerebellum) were significantly lower among alcoholics than in controls. Extrastriatal D2-receptor occupancy ratios (temporal pole/cerebellum) were not significantly different between the groups. CONCLUSIONS: Striatal presynaptic DAT densities are decreased among type 1 alcoholics, and this finding is not associated with recent alcohol abuse.

Z-IQNP: a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease.

RATIONALE: The density of the M2 subtype of muscarinic acetylcholine receptors (mAChR) has been shown to be reduced in the brain of patients with Alzheimer's disease (AD). It is therefore of interest to develop a brain imaging method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo1-propen-3-yl)-alpha-phenylacetat e (Z-IQNP) is a muscarinic antagonist with high affinity for the M2 subtype. OBJECTIVE: The pharmacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro and in vivo. METHODS: Z-IQNP was labelled with 1251 and 123I. Autoradiography was performed on whole-hemisphere cryosections from human post mortem brains. SPECT was performed in a cynomolgus monkey. RESULTS: Autoradiography showed binding of [125I]Z-IQNP in all brain regions, which was inhibited by the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [125I]Z-IQNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [123I]Z-IQNP in all brain regions. The binding was markedly reduced in all brain regions after pretreatment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [123I]Z-IQNP binding in the cerebellum, which is consistent with a high density of M2-receptors in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo. CONCLUSIONS: This study indicates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M2 than the M1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [123I]Z-IQNP should be useful for future SPECT studies in AD for examination of the density of M2 receptors particularly in the cerebellum.

Reduced serotonin transporter binding in binge eating women.

RATIONALE: There is evidence that abnormalities in brain dopamine, norepinephrine and serotonin metabolism may play an important role in binge eating. Serotonin-active antidepressant drugs have also been found to decrease binge eating. OBJECTIVE: We investigated serotonin transporter binding in obese binge-eating women. Eleven obese binge-eating and seven obese control women participated in the study. The subjects were not taking any medication known to affect serotonin (5-HT) transporters. METHODS: We used single-photon emission tomography (SPECT) with the radioligand 123I-labelled nor-beta-CIT, which specifically labels 5-HT transporters. RESULTS: Obese binge-eating women showed significantly decreased 5-HT transporter binding in the mid-brain compared with obese controls (2.1 +/- 0.5 versus 2.9 +/- 0.5, respectively). CONCLUSIONS: SPECT imaging with a ligand specific for 5-HT transporters can be used to assess altered serotonin transporter binding in the living human brain. The results tentatively suggest that 5-HT transporter binding is decreased in binge-eating women.

Abnormal structure of human striatal dopamine re-uptake sites in habitually violent alcoholic offenders: a fractal analysis.

Both animal and human studies imply that aggressive behaviour is associated with increased dopaminergic transmission. Our hypothesis was that impulsive violent offenders have also higher heterogeneity of the striatal dopamine transporter (DAT) density than controls. We performed a fractal analysis in 21 impulsive violent offenders, 10 non-violent alcoholics and 21 controls to measure the heterogeneity and laterality of the striatal DAT density characterised by [123I]beta-CIT single-photon emission tomography (SPET). The [123I]beta-CIT distribution was significantly more heterogeneous in the right striatum of violent offenders than in healthy controls. In addition, in young violent offenders there was no normal left-to-right asymmetry observed in control subjects of the same age. The normalisation of the left-to-right asymmetry may reflect late neurobiological maturation.

Specific binding and laterality of human extrastriatal dopamine D2/D3 receptors in late onset type 1 alcoholic patients.

Late onset type 1 alcoholism has been suggested to be associated with decreased dopaminergic transmission. Our hypothesis was that late onset type 1 alcoholics have also abnormal extrastriatal dopamine D(2)/D(3) receptor distribution. We performed binding, heterogeneity and laterality analysis of extrastriatal and striatal dopamine D(2)/D(3) receptors in nine late onset male alcoholics and in 12 age-matched healthy males. A radioligand, [(123)I]epidepride was used in high resolution single-photon emission tomography (SPET). Specific binding of epidepride in the left temporal pole was significantly (P<0.05) lower in type 1 alcoholics (0.74+/-0.14 ml/ml) than in controls (0.89+/-0.14 ml/ml). In alcoholics, there was no normal left-to-right asymmetry of the temporal cortical heterogeneity of epidepride distribution observed in control males (0.89+/-0.19 vs. 1.10+/-0.19; P<0.05). The results suggest that the specific binding of dopamine D(2)/D(3) receptors in late type 1 alcoholics is decreased and its laterality in the temporal brain is altered from normal.

Evaluation and metabolite studies of 125I- and 123I-labelled E-(R,R)-IQNP: potential radioligands for visualization of M1 muscarinic acetylcholine receptors in brain.

A new ligand for the M1 muscarinic receptor subtype, E-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (E-IQNP), was labelled with 125I and 123I for autoradiographic studies on human whole-brain cryosections and SPET studies, respectively, in Cynomolgus monkey. Autoradiography demonstrated E-[125I]IQNP binding in M1 receptor-rich regions such as the neocortex and the striatum. The binding was displaceable by the selective M1 antagonist biperiden. In vivo single photon emission tomography (SPET) studies with E-[123I]IQNP demonstrated a high accumulation of radioactivity in the monkey neocortex. Rapid hydrolysis of the quinuclidinyl ester to the free acid was found to be a major biotransformation route for E-[123I]IQNP. The free acid of E-[123I]IQNP does not pass the blood-brain barrier, but the plasma concentration was high as compared to the total radioactivity in brain. It is thus necessary to correct for the high concentration of radioactive metabolites in parenchymal blood (CBV) to obtain accurate values for E-[123I]IQNP binding in brain.

Striatal Dopamine transporter in Parkinson's disease: A Study With a New Radioligand, [(123)I]B-CIT-FP.

Six healthy controls and 12 patients with Parkinson's disease in different disability stages were studied with SPECT using [(123)I]-N-(3-fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodo-phenyl)-nortropane ([(123)I]beta-CIT-FP), a novel tracer, to label the striatal dopamine transporter. The mean uptake of [(123)I]beta-CIT-FP in the putamen was reduced to 60% of the control mean and to 80% of the average control value in the caudate nucleus. In patients with totally, or predominantly unilateral symptoms the reduction was greater on the side opposite to the predominant symptoms. There was a significant negative correlation between [(123)I]beta-CIT-FP uptake and the Hoehn and Yahr stage both in the putamen (r = - 0.70, p = 0.01) and caudate nucleus (r = - 0.81, p = 0.001). The present results show that SPECT with [(123)I]beta-CIT-FP is a useful method to study the function of presynaptic dopaminergic terminals in PD. Whether [(123)I]beta-CIT-FP provides advantages over widely used [(123)I]beta-CIT other than a shorter scan time and a lower striatal radiation exposure remains to be seen.

Striatal dopamine transporter in different disability stages of Parkinson's disease studied with [(123)I]beta-CIT SPECT.

Six healthy controls and eighteen patients with Parkinson's disease in different disability stages were studied with SPECT using [(123)I]beta-CIT to label the striatal dopamine transporter. The mean uptake of [(123)I]beta-CIT in the putamen was reduced to 54% of the control mean and to 65% of the average control value in the caudate nucleus. In patients with totally, or predominantly unilateral symptoms the reduction was greater on the side opposite to the predominant symptoms (to 56% of the control mean in the contralateral putamen and to 77% in the ipsilateral putamen). There was a significant negative correlation between [(123)I]beta-CIT uptake in the putamen and the Hoehn and Yahr stage (r = -0.81, p < 0.0001). An analysis of covariance was performed using age and disease duration as covarianes, and the correlation between putaminal [(123)I]beta-CIT uptake and parkinsonian disability according to the Hoehn and Yahr stage remained significant (r = -0.75, p = 0.02). A similar correlation was seen in the caudate nucleus (r = -0.79, p < 0.0001) between the uptake of [(123)I]beta-CIT and the Hoehn and Yahr stage. The correlation also remained significant after correction for the duration of disease and age of the patients (r= -0.76, p = 0.02). The present results show that [1231],Q-CIT SPECT is a useful method to study the function of presynaptic dopaminergic terminals in PD, and might be used in the early diagnosis and follow-up of the disease.

Comparison of HPLC, TLC and minicolumn for measuring the radiochemical purity of 99Tcm-Q12.

TechneScan Q12 (99Tcm-Q12) is a new agent for clinical myocardial perfusion imaging. A product with high radiochemical purity is essential for high-quality imaging. We compared three methods of radiochemical purity analysis for 99Tcm-Q12: thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) and minicolumn. Thin-layer chromatography resulted in lower purity (87 +/- 8%) than the minicolumn method (aluminium oxide minicolumn, ethanol) (95 +/- 4%). The HPLC method resulted in the lowest purity (79 +/- 11%). The main impurity was a polar compound, but three further impurities were found using HPLC. Using HPLC, we found the percentage of the parent compound (99Tcm-Q12) in plasma at 40-90 min post-injection to be 19.3 +/- 6.2%. We suggest that gradient HPLC is the most effective method for the analysis of the radiochemical purity of 99Tcm-Q12, and that it can be used to determine the concentration of 99Tcm-Q12 in plasma.

Effect of radiochemical purity of 99Tcm-Q12 on myocardial SPET image quality.

In myocardial perfusion SPET studies with 99Tcm-Q12, we observed that some patients had high liver uptake that interfered significantly in the assessment of the inferior wall. The aim of this study was to assess the effects of the radiochemical purity of 99Tcm-Q12 on liver uptake. Thirty-one patients undergoing routine myocardial infarction perfusion studies were evaluated. The radiochemical purity of 99Tcm-Q12 was determined using HPLC. Venous blood samples taken 50 min after injection of 99Tcm-Q12 during peak exercise were also analysed. Liver uptake was expressed as the liver-to-heart ratio. In addition, the SPET images were classified by two experienced nuclear medicine specialists into three groups representing high-quality images (n = 7), images with high general background activity (n = 13) and images with high liver and/or intestinal uptake (n = 11). The liver-to-heart ratio correlated inversely with the radiochemical purity of 99Tcm-Q12 (r = -0.65, P < 0.001) and unchanged 99Tcm-Q12 in plasma (r = -0.44, P < 0.02). The radiochemical purity of 99Tcm-Q12 was significantly lower in the group with high liver uptake (60.1 +/- 4.2%) than in the group with good-quality images (81.8 +/- 5.6%, P < 0.01) or with high background activity (82.3 +/- 2.5%, P < 0.01). In conclusion, the radiochemical purity of 99Tcm-Q12 has a significant inverse correlation with the liver-to-heart ratio; thus, the high radiochemical purity of 99Tcm-Q12 should be confirmed to prevent interference by liver uptake.

Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder.

The neuroanatomical networks involved in the initiation of panic attack and the maintenance of panic disorder are poorly understood. This study aimed to elucidate the possible abnormalities in benzodiazepine receptor uptake in the brain of patients with panic disorder. Seventeen unmedicated patients with panic disorder were investigated using 123I-iomazenil single photon emission tomography (SPET). Seventeen healthy age- and sex-matched volunteers served as controls. The SPET scan was taken 90 min after injection of tracer. Eleven of 17 patients (65%) showed an increased (> 2 S.D. higher than the mean of the controls) right-to-left ratio of benzodiazepine receptor uptake in the prefrontal cortex. Also, the mean right-to-left ratio of benzodiazepine receptor uptake in all 17 patients with panic disorder was higher than in the controls (P < 0.001). Our SPET study demonstrated focally altered benzodiazepine receptor uptake in the prefrontal cortices in patients with panic disorder. Magnetic resonance imaging indicated that the affected region was located in the right middle and inferior frontal gyri. The deterioration in information processing in the right prefrontal cortex may be implicated in the generation of panic disorder.

Effect of trail design and grooming on the incidence of injuries at alpine ski areas.

OBJECTIVES: To identify the conditions at certain sites on slopes known as black spots for injury. METHOD: In the Hafjell and Voss alpine ski areas in Norway, 1410 skiing injuries were recorded from December 1990 through the 1996 season. In Hafjell, 183 of these injuries were plotted on an area map during the two first seasons. Similarly, in Voss, 214 injuries were plotted on an area map for two seasons. During the last three seasons in Hafjell, 835 ski injuries were related to 6712 snow grooming hours and 6,829,084 lift journeys. RESULTS: The mean injury rate was 2.2 injuries per 1000 skier days, and the mean injury severity score (ISS) was 3.1. Accumulations of injuries at three sites (black spots) were recorded on the Hafjell area map. These injuries represented 40% of all injuries in the alpine area (p<0.05). Seven injury accumulation sites were recorded on the alpine area map of Voss, representing 22% of the total injuries (p>0.05). Grooming of the slopes was rated poor for the 49% of injuries that occurred at the sites of injury concentration and significantly different (27%) from injuries that occurred at random in Hafjell. The corresponding values in Voss were 50% and 25% respectively. Grooming hours appeared to be inversely proportional to the number of injuries: R = -0.99 (p<0.02). The mean ISS declined significantly in Hafjell over the observation period (p<0.001). CONCLUSION: Inappropriate trail design and slope grooming seem to result in an accumulation of injuries at certain sites. Modification in construction and maintenance of the courses may reduce the number of injuries and mean ISS.

Detection of focal inflammation with Tc-99m HMPAO labeled leukocytes in children.

To evaluate the applicability of Tc-99m HMPAO leukocyte scintigraphy in the assessment of focal infections in children, we retrospectively analyzed 26 studies performed between 1988 and 1992. All patients (n = 25, age range 1 month-15 years) were severely ill and suspected to have invasive bacterial infection. In each case, whole body scintigraphy was performed 2-4 hours after injection of autologous labeled leukocytes. There were 8 true positive and 14 true negative cases; specificity was 88% and sensitivity 80%. The two false negative findings were observed in patients on immunosuppressive therapy; both had fungal infections. In one case, atypical non-specific bowel accumulation of the tracer was falsely interpreted as an abscess. The other false positive finding was hip accumulation in a patient who later turned out to have Mucha-Haberman disease; transient synovitis may explain the finding. Of the eight true positive cases, six had an invasive infection focus and two had an aseptic inflammatory process. Tc-99m HMPAO leukocyte scintigraphy is a valuable method in the assessment of focal inflammation in children, including infants.

Dopamine transporter in vitro binding and in vivo imaging in the brain.

Much research interest has lately been focused on the dopamine transporter function in brain. Recent findings indicate that dopamine reuptake is more like a highly regulated than a constitutive determinant of dopamine clearance. Positron emission tomography (PET) and single-photon emission tomography (SPET) offer unique methods to study dopamine transporter function. Results from in vivo PET and SPET studies correspond well with in vitro studies performed on post mortem human brain tissue. Considering some of the variances between in vitro and in vivo receptor binding phenomena it may be that the role of a compound to alter binding to monoamine uptake sites in vitro does not indicate its potential to affect monoamine transporters after administration in vivo. This discrepancy may be better understood taking into account recent studies indicating the possibility of a rapid regulation of transporter function and surface expression. Furthermore, the dopamine transporter is a fruitful target for CNS drug discovery. Fundamental nature of drug actions in vivo may be studied using demonstrated in vitro and in vivo imaging methods.

Organisation of safety measures in an Alpine World Junior Championship.

OBJECTIVES: To study the implementation of skiing safety during the Alpine World Junior Championship of 1995. METHODS: A map of the area was made with descriptions of the slopes and all its facilities and the security measures along the course. The number of competitors who started and any injuries reported were recorded in a questionnaire. RESULTS: A total of 452 girls and 546 boys started in the different races. Only four injuries were recorded, all in girls. The overall injury rate was 4 per 1000 runs. An injury rate of 8.3 per 1000 runs was recorded in the downhill. One skier had a possibly severe injury (ISS = 14) in the downhill; the rest of the injuries were minor (ISS = 1). The mean ISS was 4.3 and the total ISS was 17. CONCLUSIONS: A significantly higher injury rate was recorded for young female than young male racers. The injury rate was significantly higher in downhill than the other alpine disciplines in the Alpine World Junior Championship. The injury rate was not significantly different from that recorded one year previously for Olympic racers, and juniors therefore need the same safety measures as Olympic racers.

The dosimetry of iodine-123 labelled 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane.

This report documents the radiation dosimetry of iodine-123 labelled 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane [123I]beta-CIT in humans. The mean absorbed doses for various organs and the effective dose equivalent were estimated from whole-body scans, blood samples and single-photon emission tomography scans acquired up to 22 h after the injection of a known amount of tracer. The basal ganglia, the liver and the lower large intestinal wall received the highest mean absorbed doses of 0.270 mGy/MBq, 0.038 mGy/MBq and 0.034 mGy/MBq, respectively. The effective dose equivalent for adults was estimated using 11 organs and the ICRP-87 radiation dose model and was 0.031 mSv/MBq. The radiation dose to the basal ganglia limits the maximum injected activity of [125I]beta-CIT to 185 MBq for a single study.

Fractal analysis of striatal dopamine re-uptake sites.

Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]beta-CIT). The mean fractal dimension was 1.15+/-0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19+/-0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions.

Activity-related knee injuries and pain in athletic adolescents.

By collecting data from 45 students at a ski high school, we found that a total of 73% of the students reported activity-related pain/injuries of the knee. Sixty-one percent had overuse injuries, 27% malalignment, and 12% had indistinct knee pain. Females suffered more knee pain/injuries (88%) than males (57%). Significantly higher Q-angle degrees were recorded for females (16) than for males (10). "Jumper's knee" was found in all competitive students with a KT manual maximum difference (MMD) of 3 mm or more (mean 4 mm), with a hard endpoint, whereas this was less common among the other competitive students (P < 0.05). The students were given counselling about training and physiotherapy. In the follow-up study 1 year later, a significant reduction of knee pain/overuse injuries, from 73% to 35%, was recorded. This may be related to better equipment, the development of techniques, and training of the muscles. A high volume of training and knee instability, with MMD of 3 mm or more, seemed to be correlated with an increased risk for "jumper's knee" and, possibly, for skiing injuries. By identifying those at increased risk, preseason recommendations can be made and ski injuries may be prevented.

Initial experience with single-photon emission tomography using iodine-123-labelled 2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane in human brain.

The iodinated cocaine analogue 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT), a new dopamine transporter, was preliminary tested in human brain. Two normal volunteers and two patients with Parkinson's disease were imaged with a high-resolution single-photon emission tomography scanner. The specific binding of [123I]beta-CIT in the basal ganglia and thalamus was high in normal volunteers. In addition, there was relatively intense uptake in the medial prefrontal area. Patients with Parkinson's disease who were older than controls showed significantly lower specific binding in the basal ganglia and thalamus and no uptake in the medial prefrontal cortex. This decrease in the dopamine transporter may be age related.