Reduction in camera-specific variability in [(123)I]FP-CIT SPECT outcome measures by image reconstruction optimized for multisite settings: impact on age-dependence of the specific binding ratio in the ENC-DAT database of healthy controls.

PURPOSE: Quantitative estimates of dopamine transporter availability, determined with [(123)I]FP-CIT SPECT, depend on the SPECT equipment, including both hardware and (reconstruction) software, which limits their use in multicentre research and clinical routine. This study tested a dedicated reconstruction algorithm for its ability to reduce camera-specific intersubject variability in [(123)I]FP-CIT SPECT. The secondary aim was to evaluate binding in whole brain (excluding striatum) as a reference for quantitative analysis. METHODS: Of 73 healthy subjects from the European Normal Control Database of [(123)I]FP-CIT recruited at six centres, 70 aged between 20 and 82 years were included. SPECT images were reconstructed using the QSPECT software package which provides fully automated detection of the outer contour of the head, camera-specific correction for scatter and septal penetration by transmission-dependent convolution subtraction, iterative OSEM reconstruction including attenuation correction, and camera-specific "to kBq/ml" calibration. LINK and HERMES reconstruction were used for head-to-head comparison. The specific striatal [(123)I]FP-CIT binding ratio (SBR) was computed using the Southampton method with binding in the whole brain, occipital cortex or cerebellum as the reference. The correlation between SBR and age was used as the primary quality measure. RESULTS: The fraction of SBR variability explained by age was highest (1) with QSPECT, independently of the reference region, and (2) with whole brain as the reference, independently of the reconstruction algorithm. CONCLUSION: QSPECT reconstruction appears to be useful for reduction of camera-specific intersubject variability of [(123)I]FP-CIT SPECT in multisite and single-site multicamera settings. Whole brain excluding striatal binding as the reference provides more stable quantitative estimates than occipital or cerebellar binding.

Implementation of the European multicentre database of healthy controls for [(123)I]FP-CIT SPECT increases diagnostic accuracy in patients with clinically uncertain parkinsonian syndromes.

PURPOSE: Even though [(123)I]FP-CIT SPECT provides high accuracy in detecting nigrostriatal cell loss in neurodegenerative parkinsonian syndromes (PS), some patients with an inconclusive diagnosis remain. We investigated whether the diagnostic accuracy in patients with clinically uncertain PS with previously inconclusive findings can be improved by the use of iterative reconstruction algorithms and an improved semiquantitative evaluation which additionally implemented a correction algorithm for patient age and gamma camera dependency (EARL-BRASS; Hermes Medical Solutions, Sweden). METHODS: We identified 101 patients with inconclusive findings who underwent an [(123)I]FP-CIT SPECT between 2003 and 2010 as part of the diagnostic process of suspected PS at the University of Munich, and re-evaluated these scans using iterative reconstruction algorithms and the new corrected EARL-BRASS. Clinical follow-up was obtained in 62 out of the 101 patients and constituted the gold standard for the re-evaluation to assess the possible improvement in diagnostic accuracy. RESULTS: Clinical follow-up confirmed the diagnosis of PS in 11 of the 62 patients. In patients in whom both visual and semiquantitative analysis showed concordant findings (48 patients), a high negative predictive value (93 %), positive predictive value (100 %) and accuracy (94 %) were found, and thus a correct diagnosis was obtained in 45 of the 48 patients. Among the 14 patients with discordant findings, the additional semiquantitative analysis correctly identified all five of nine patients patients without PS by nonpathological semiquantitative findings in visually pathological or inconclusive scans. In contrast, four of the remaining five patients with decreased semiquantitative values but visually normal scans did not show a PS during follow-up. CONCLUSION: The age-corrected and camera-corrected mode of evaluation using EARL-BRASS provided a notable improvement in the diagnostic accuracy of [(123)I]FP-CIT SPECT in PS patients with previously inconclusive findings. The gain in accuracy might be achieved by better discrimination between physiological low striatal [(123)I]FP-CIT binding due to age-related loss of the dopamine transporter or pathological loss of binding.

Extrastriatal binding of [¹²³I]FP-CIT in the thalamus and pons: gender and age dependencies assessed in a European multicentre database of healthy controls.

PURPOSE: Apart from binding to the dopamine transporter (DAT), [(123)I]FP-CIT shows moderate affinity for the serotonin transporter (SERT), allowing imaging of both monoamine transporters in a single imaging session in different brain areas. The aim of this study was to systematically evaluate extrastriatal binding (predominantly due to SERT) and its age and gender dependencies in a large cohort of healthy controls. METHODS: SPECT data from 103 healthy controls with well-defined criteria of normality acquired at 13 different imaging centres were analysed for extrastriatal binding using volumes of interest analysis for the thalamus and the pons. Data were examined for gender and age effects as well as for potential influence of striatal DAT radiotracer binding. RESULTS: Thalamic binding was significantly higher than pons binding. Partial correlations showed an influence of putaminal DAT binding on measured binding in the thalamus but not on the pons. Data showed high interindividual variation in extrastriatal binding. Significant gender effects with 31 % higher binding in women than in men were observed in the thalamus, but not in the pons. An age dependency with a decline per decade (±standard error) of 8.2 ± 1.3 % for the thalamus and 6.8 ± 2.9 % for the pons was shown. CONCLUSION: The potential to evaluate extrastriatal predominant SERT binding in addition to the striatal DAT in a single imaging session was shown using a large database of [(123)I]FP-CIT scans in healthy controls. For both the thalamus and the pons, an age-related decline in radiotracer binding was observed. Gender effects were demonstrated for binding in the thalamus only. As a potential clinical application, the data could be used as a reference to estimate SERT occupancy in addition to nigrostriatal integrity when using [(123)I]FP-CIT for DAT imaging in patients treated with selective serotonin reuptake inhibitors.

No association between striatal dopamine transporter binding and body mass index: a multi-center European study in healthy volunteers.

INTRODUCTION: Dopamine is one among several neurotransmitters that regulate food intake and overeating. Thus, it has been linked to the pathophysiology of obesity and high body mass index (BMI). Striatal dopamine D(2) receptor availability is lower in obesity and there are indications that striatal dopamine transporter (DAT) availability is also decreased. In this study, we tested whether BMI and striatal DAT availability are associated. METHODS: The study included 123 healthy individuals from a large European multi-center database. They had a BMI range of 18.2-41.1 kg/m(2) and were scanned using [(123)I]FP-CIT SPECT imaging. Scans were analyzed with both region-of-interest and voxel-based analysis to determine the binding potential for DAT availability in the caudate nucleus and putamen. A direct relation between BMI and DAT availability was assessed and groups with high and low BMI were compared for DAT availability. RESULTS: No association between BMI and striatal DAT availability was found. CONCLUSION: The lack of an association between BMI and striatal DAT availability suggests that the regulation of striatal synaptic dopamine levels by DAT plays no or a limited role in the pathophysiology of overweight and obesity.

European multicentre database of healthy controls for [123I]FP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis.

PURPOSE: Dopamine transporter (DAT) imaging with [(123)I]FP-CIT (DaTSCAN) is an established diagnostic tool in parkinsonism and dementia. Although qualitative assessment criteria are available, DAT quantification is important for research and for completion of a diagnostic evaluation. One critical aspect of quantification is the availability of normative data, considering possible age and gender effects on DAT availability. The aim of the European Normal Control Database of DaTSCAN (ENC-DAT) study was to generate a large database of [(123)I]FP-CIT SPECT scans in healthy controls. METHODS: SPECT data from 139 healthy controls (74 men, 65 women; age range 20-83 years, mean 53 years) acquired in 13 different centres were included. Images were reconstructed using the ordered-subset expectation-maximization algorithm without correction (NOACSC), with attenuation correction (AC), and with both attenuation and scatter correction using the triple-energy window method (ACSC). Region-of-interest analysis was performed using the BRASS software (caudate and putamen), and the Southampton method (striatum). The outcome measure was the specific binding ratio (SBR). RESULTS: A significant effect of age on SBR was found for all data. Gender had a significant effect on SBR in the caudate and putamen for the NOACSC and AC data, and only in the left caudate for the ACSC data (BRASS method). Significant effects of age and gender on striatal SBR were observed for all data analysed with the Southampton method. Overall, there was a significant age-related decline in SBR of between 4 % and 6.7 % per decade. CONCLUSION: This study provides a large database of [(123)I]FP-CIT SPECT scans in healthy controls across a wide age range and with balanced gender representation. Higher DAT availability was found in women than in men. An average age-related decline in DAT availability of 5.5 % per decade was found for both genders, in agreement with previous reports. The data collected in this study may serve as a reference database for nuclear medicine centres and for clinical trials using [(123)I]FP-CIT SPECT as the imaging marker.

Dopamine transporter imaging in autopsy-confirmed Parkinson's disease and multiple system atrophy.

Dopamine transporter single-photon emission computerized tomography can visualize dopaminergic degeneration in Parkinson's disease and multiple system atrophy. Some studies have suggested that dopamine transporter imaging can distinguish these disorders based on a more diffuse and symmetric striatal dopamine transporter binding loss in multiple system atrophy. The present study compared patterns of striatal dopamine transporter distribution in postmortem-confirmed Parkinson's disease and multiple system atrophy. Patients with a postmortem diagnosis of multiple system atrophy (n = 6) or Parkinson's disease (n = 8) who had undergone dopamine transporter imaging were included. Imaging had been performed after a mean disease duration of 3.6 and 4.1 years in multiple system atrophy and Parkinson's disease, respectively. Visual analysis showed bilaterally reduced binding in all patients. Mean overall striatal binding was reduced by 53% in multiple system atrophy and 52% in Parkinson's disease. There was a trend for greater asymmetry of striatal binding in multiple system atrophy compared with Parkinson's disease (23% ± 15% vs 10.5% ± 7%, respectively; P = .071), with 3 multiple system atrophy patients showing more asymmetry of striatal binding than any Parkinson's disease patient. Putamen/caudate binding ratios did not differ between the groups. This is the first study comparing dopamine transporter imaging in autopsy-confirmed multiple system atrophy and Parkinson's disease. Unexpectedly, we found a tendency for greater asymmetry of striatal binding in multiple system atrophy than in Parkinson's disease. Our findings demonstrate that these conditions cannot be differentiated by subregional analysis of striatal dopamine transporter binding.

Value of 1H-magnetic resonance spectroscopy chemical shift imaging for detection of anaplastic foci in diffusely infiltrating gliomas with non-significant contrast-enhancement.

OBJECTIVE: In diffusely infiltrating gliomas (DIG), positron emission tomography (PET) imaging is a powerful method for detection of anaplastic foci. Recently, (1)H-magnetic resonance spectroscopy chemical shift imaging (CSI) using choline/creatine (Cho/Cr) or choline/N-acetylaspartate (Cho/NAA) ratios has emerged as a new non-invasive, widely available alternative. The authors therefore correlated CSI with (11)C-methionine (MET)-PET data in a series of DIG with non-significant contrast-enhancement (CE). METHODS: Thirty-two patients with DIG were examined with single-slice CSI on a T MRI and MET-PET. Maximum pathological intratumoural ratios of CSI (=CSI(max)) and maximum tumour-to-normal-brain PET ratios (=PET(max); T/N ratio) were determined. Coregistration of MRI with CSI and PET was performed, and the topographic overlap of CSI(max) and PET(max) was analysed. Histological criteria of anaplasia as well as cell proliferation rate were assessed in tumour samples inside and outside CSI(max). RESULTS: CSI showed a pathological ratio in all patients, whereas PET demonstrated a pathological T/N ratio in 21/32 patients. Topographical correlation of CSI(max) and PET(max) revealed a ≥ 50% overlap in 18/21 and <50% overlap in 3/21 patients, respectively. Cho/Cr(max) and Cho/NAA(max) showed a ≥ 50% overlap in 24/32 and a <50% overlap in 8/32 patients. Cell proliferation rate was significantly higher inside than outside the CSI(max) (13.6% vs 6.9%, p<0.001). CONCLUSION: The results indicate that CSI is a promising method for detection of anaplastic foci within DIG with non-significant CE. Intraoperative use of CSI by multimodal neuronavigation may increase the reliability of detection of malignant areas in glioma surgery and therefore optimise allocation of patients to adjuvant treatments.

Central serotonin 1A receptor binding in temporal lobe epilepsy: a [carbonyl-(11)C]WAY-100635 PET study.

We performed positron emission tomography using [carbonyl-(11)C]WAY-100635, a serotonin 1A (5-HT(1A)) receptor antagonist, in 13 patients with temporal lobe epilepsy (TLE) and in 13 controls. 5-HT(1A) receptor distribution mapping allowed correct lateralization of the epileptogenic temporal lobe in all patients. 5-HT(1A) receptor binding potential (BP(ND)) was significantly reduced in almost all temporal regions of the epileptogenic lobe. Compared with controls, the patients had significantly decreased BP(ND) values in the hippocampus, parahippocampal gyrus, and amygdala. The asymmetry index (AI), which characterizes the interhemispheric asymmetry in BP(ND), was significantly higher in patients than in controls in most regions. Depression scores were not significantly correlated with BP(ND) or AI values. Our data provide further evidence of functional changes in the serotonergic system in TLE. Molecular imaging of the 5-HT(1A) receptor may help to define the in vivo neurochemistry of TLE, and may provide a valuable tool in the noninvasive presurgical assessment of patients with medically refractory TLE.

EANM procedure guidelines for PET brain imaging using [18F]FDG, version 2.

These guidelines summarize the current views of the European Association of Nuclear Medicine Neuroimaging Committee (ENC). The purpose of the guidelines is to assist nuclear medicine practitioners in making recommendations, performing, interpreting, and reporting the results of fluorine-18 fluoro-2-deoxyglucose ([(18)F]FDG) PET imaging of the brain. The aim is to help achieve a high standard of FDG imaging, which will increase the diagnostic impact of this technique in neurological and psychiatric practice. The present document replaces a former version of the guidelines that were published in 2002 [1] and includes an update in the light of advances in PET technology, the introduction of hybrid PET/CT systems and the broadening clinical indications for FDG brain imaging. These guidelines are intended to present information specifically adapted for European practice. The information provided should be taken in the context of local conditions and regulations.

Higher serotonin transporter occupancy after multiple dose administration of escitalopram compared to citalopram: an [123I]ADAM SPECT study.

OBJECTIVES: Previous studies have investigated the occupancy of the serotonin reuptake transporter (SERT) after clinical doses of citalopram and other selective serotonin reuptake inhibitors. In the present study, the occupancies of SERT after multiple doses of escitalopram and citalopram were compared using the radioligand [(123)I]ADAM and single photon emission computed tomography (SPECT). METHODS: Fifteen healthy subjects received escitalopram 10 mg/day (n = 6) or citalopram 20 mg/day (n = 9) for a total of 10 days. SERT occupancies in midbrain were determined with SPECT and [(123)I]ADAM at three different time points: at baseline (no medication) and at 6 and 54 h after last drug intake. RESULTS: At 6 h after the last dose, mean SERT occupancies were 81.5 +/- 5.4% (mean+/-SD) for escitalopram and 64.0 +/- 12.7% for citalopram (p < 0.01). At 54 h after the last dose, mean SERT occupancies were 63.3 +/- 12.1% for escitalopram and 49.0 +/- 11.7% for citalopram (p < 0.05). The plasma concentrations of the S-enantiomer were of the same magnitude in both substances. For both drugs, the elimination rate of the S-enantiomer in plasma was markedly higher than the occupancy decline rate in the midbrain. CONCLUSION: The significantly higher occupancy of SERT after multiple doses of escitalopram compared to citalopram indicates an increased inhibition of SERT by escitalopram. The results can also be explained by an attenuating effect of R-citalopram on the occupancy of S-citalopram at the SERT.

Striatal D(2) receptor occupancy in bipolar patients treated with olanzapine.

We explored the relationship between striatal dopamine-2 (D(2)) receptor occupancy and extra-pyramidal symptoms (EPS) in bipolar patients receiving olanzapine. Seventeen patients with a DSM-IV diagnosis of bipolar disorder were treated with 5-45 mg/day olanzapine for at least 14 days. After that period, D(2) receptor occupancy was determined using Iodobenzamide (IBZM) and SPECT. EPS were assessed by the Simpson-Angus Scale (SAS) and Barnes-Akathisia Scale (BAS). We found a dose-dependent increase in occupancy: 5 mg led to 28-50%, 10 mg to 40-68%, 15 mg to 69%, 20 mg to 57-66%, 30 mg to 66% and 45 mg to 80% D(2) receptor occupancy; and a significant correlation between plasma levels and occupancy (R(2)=.55, P=.001). Similar to schizophrenic patients, bipolar patients did not exhibit EPS at D(2) occupancy levels of 28 to 80%. Although we did not find an increased vulnerability for acute EPS in bipolar patients receiving olanzapine at clinical relevant doses, this needs to be replicated with larger sample sizes.

Modern imaging methods for the assessment of Langerhans' cell histiocytosis-associated neurodegenerative syndrome: case report.

Langerhans' cell histiocytosis-associated neurodegenerative syndrome is an enigmatic manifestation, most often localized in the cerebellum and the basal ganglia. Its pathophysiologic basis is poorly understood, and effective treatment strategies are currently missing. Modern imaging modalities offer the possibility of shedding further light on this puzzling disease in a noninvasive way. We report on a 12-year-old boy with a Langerhans' cell histiocytosis-associated neurodegenerative syndrome who underwent a thorough evaluation with different modern imaging methods in addition to routine brain magnetic resonance imaging (MRI) to analyze their informative value for this condition. Additional imaging included positron emission tomography using [18F]fluorodeoxyglucose (FDG-PET), single photon emission computed tomography using [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane and [123I]iodobenzamide, and magnetic resonance spectroscopy. The potential relevance of each method for neurodegenerative Langerhans' cell histiocytosis is discussed based on the results obtained, and a review of the literature is made. The case underlines the fact that MRI undoubtedly possesses the major role in the diagnostic evaluation and monitoring of Langerhans' cell histiocytosis-associated neurodegenerative syndrome. FDG-PET and magnetic resonance spectroscopy findings were in good correlation with the MRI results. In particular, magnetic resonance spectroscopy could provide a valuable diagnostic tool in addition to MRI in the early detection and evaluation of the neurodegenerative component of this disease.

Low cerebrovascular reserve capacity in long-term follow-up after subarachnoid hemorrhage.

BACKGROUND: Intradural arteries formerly in vasospasm after subarachnoid hemorrhage (SAH) show structural changes that result in arterial wall thickening and luminal narrowing. To evaluate if these changes lead to maldistribution of cerebral perfusion and reduced cerebrovascular reserve capacity (CVRC) in surviving patients, a long-term follow-up study of 18 adult patients after SAH was performed. METHODS: Eighteen patients were selected for the study, all had shown vasospasm after an early operation on a ruptured aneurysm, were in good neurological condition (GOS [Glasgow Outcome Score] 4 or 5 ), and had no residual infarcts. A technetium-99m-hexamethyl-propylenamine oxime (HMPAO) single-photon emission computed tomography was performed 15 to 73 months after SAH. To study CVRC, a second investigation after application of acetazolamide was performed 1 week later. RESULTS: Single-photon emission computed tomography showed areas of focally reduced HMPAO uptake predominantly in the hemisphere ipsilateral to the vessels more affected by posthemorrhagic vasospasm. The thalamus and the basal ganglia, the frontal lobe, and the temporal lobe were the regions most frequently showing reduced uptake. The individual change of HMPAO uptake after acetazolamide application ranged from -7% to 44% (mean, 17% +/- 15%). CONCLUSIONS: These results show a remarkable reduction of CVRC compared with findings in healthy individuals. Based on these new findings, further investigations focusing on CVRC in routine SAH follow-up are worth being considered.

Striatal dopamine-2 receptor occupancy as measured with [123I]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol.

RATIONALE: Extrapyramidal symptoms (EPS) are common with conventional antipsychotics. Clozapine and other novel antipsychotic substances with lower in vitro affinity for dopamine-2 (D(2)) receptors have a lower propensity to induce EPS. OBJECTIVE: We investigated whether striatal D(2) receptor occupancy predicted the occurrence of EPS with atypical antipsychotics and the typical neuroleptic haloperidol. METHODS: [(123)I]Iodobenzamide (IBZM) and single photon emission tomography (SPECT) were used to quantify receptor occupancy in 71 patients treated with antipsychotics. EPS were rated according to the Simpson-Angus scale (SAS). EPS were deemed clinically relevant, if the SAS score was > or = 5 and/or anticholinergic medication was required. Patients received atypical antipsychotic monotherapy for at least 14 days with amisulpride ( n=2), clozapine ( n=6), haloperidol ( n=10), olanzapine ( n=6), quetiapine ( n=4), risperidone ( n=14), sertindole ( n=13), or zotepine ( n=16). RESULTS: The striatal D(2) receptor occupancy ranged from < 20% to almost saturation. The lowest occupancy was seen with quetiapine and clozapine, the highest with haloperidol. Twenty-two of 71 patients (29%) experienced clinically relevant EPS. These patients displayed significantly higher mean striatal D(2) receptor occupancy (77%) than those without EPS (61%; P=0.002). We found a positive correlation between the percentage of striatal D(2) receptor occupancy and the SAS score ( r=0.28; P=0.02), despite 18 of these patients receiving anticholinergics, thus lowering their SAS score. CONCLUSIONS: Striatal D(2) receptor occupancy as measured with [(123)I]IBZM and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol. In vivo imaging of brain receptors with SPECT may provide a useful clinical tool to titrate doses individually and avoid motor side effects in patients treated with novel antipsychotics.

Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder--implications for psychopharmacology.

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 Tourette's disorder. Striatal D2 and 5-HT1A receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naïve 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 5-HT1A receptors in drug-naïve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HT1A receptor binding potential in schizophrenia. beta-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 [123I] beta-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 beta-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 Tourette's 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 drug-naïve TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments.

Association of central serotonin transporter availability and body mass index in healthy Europeans.

UNLABELLED: Serotonin-mediated mechanisms, in particular via the serotonin transporter (SERT), are thought to have an effect on food intake and play an important role in the pathophysiology of obesity. However, imaging studies that examined the correlation between body mass index (BMI) and SERT are sparse and provided contradictory results. The aim of this study was to further test the association between SERT and BMI in a large cohort of healthy subjects. METHODS: 127 subjects of the ENC DAT database (58 females, age 52 ± 18 years, range 20-83, BMI 25.2 ± 3.8 kg/m(2), range 18.2-41.1) were analysed using region-of-interest (ROI) and voxel-based approaches to calculate [(123)I]FP-CIT specific-to-nonspecific binding ratios (SBR) in the hypothalamus/thalamus and midbrain/brainstem as SERT-specific target regions. RESULTS: In the voxel-based analysis, SERT availability and BMI were positively associated in the thalamus, but not in the midbrain. In the ROI-analysis, the interaction between gender and BMI showed a trend with higher correlation coefficient for men in the midbrain albeit not significant (0.033SBRm(2)/kg, p=0.1). CONCLUSIONS: The data are in agreement with previous PET findings of an altered central serotonergic tone depending on BMI, as a probable pathophysiologic mechanism in obesity, and should encourage further clinical studies in obesity targeting the serotonergic system.

Dopamine D2 receptor SPECT in corticobasal syndrome and autopsy-confirmed corticobasal degeneration.

BACKGROUND: Corticobasal degeneration (CBD) is a rare neurodegenerative disorder characterized by tau-positive neuronal and glial lesions in the cortex and striatum with neuronal loss in cortical regions and in the substantia nigra. Striatal dopamine D2 receptor binding in autopsy-confirmed CBD has not been studied before. METHODS: We performed D2 receptor single photon emission computerized tomography using (123)I-IBZM in nine patients with a clinically diagnosed corticobasal syndrome (CBS) and on ten healthy controls. Two of the patients subsequently came to autopsy and were diagnosed with CBD. RESULTS: Overall striatal D2 receptor binding was preserved in 8/9 patients, but more asymmetric than in controls. Overall striatal binding in pathologically confirmed CBD was reduced in one case and normal in the other, and was lower contralateral to the clinically more affected side in both. CONCLUSION: This first study on D2 receptor imaging in autopsy-confirmed CBD demonstrates that loss of postsynaptic striatal neurons in CBD is a variable finding. Given the heterogeneity of our findings in pathology-confirmed cases, D2 receptor imaging seems to be of little practical value in the diagnostic workup of patients with CBS.

No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using [123I]FP-CIT (DaTSCAN) and SPECT.

BACKGROUND: Mesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D2-like receptors. Molecular imaging studies of the relationship between DAT availability/dopamine synthesis capacity and active cigarette smoking have shown conflicting results. Through the collaboration between 13 SPECT centres located in 10 different European countries, a database of FP-CIT-binding in healthy controls was established. We used the database to test the hypothesis that striatal DAT availability is changed in active smokers compared to non-smokers and ex-smokers. METHODS: A total of 129 healthy volunteers were included. Subjects were divided into three categories according to past and present tobacco smoking: (1) non-smokers (n = 64), (2) ex-smokers (n = 39) and (3) active smokers (n = 26). For imaging of the DAT availability, we used [123I]FP-CIT (DaTSCAN) and single photon emission computed tomography (SPECT). Data were collected in collaboration between 13 SPECT centres located in 10 different European countries. The striatal measure of DAT availability was analyzed in a multiple regression model with age, SPECT centre and smoking as predictor. RESULTS: There was no statistically significant difference in DAT availability between the groups of active smokers, ex-smokers and non-smokers (p = 0.34). Further, we could not demonstrate a significant association between striatal DAT and the number of cigarettes per day or total lifetime cigarette packages in smokers and ex-smokers. CONCLUSION: Our results do not support the hypothesis that large differences in striatal DAT availability are present in smokers compared to ex-smokers and healthy volunteers with no history of smoking.

Favourable results in treatment-resistant schizophrenic patients under combination of aripiprazole with clozapine.

Clozapine is still the gold standard in treatment-resistant schizophrenia. However, a substantial amount of patients do not fully recover on clozapine monotherapy. Though there is still a lack of randomised controlled studies of combination strategies in treatment-resistant schizophrenia, they are widely used. Aripiprazole is a relatively new therapeutic option due to its partial D2 agonism. Both clozapine and aripiprazole, though having a generally favourable side-effect profile, may lead to insufficient response and might provoke side effects in monotherapy. We report the case of four patients in whom we observed a distinct clinical improvement with respect to positive and negative symptoms without major side effects under a combination of clozapine and aripiprazole. The combination of clozapine action and aripiprazole-mediated D(2) receptor regulation could be responsible for the described favourable effects and for the increase of D(2) receptor blockade after adding aripiprazole to clozapine observed in one patient. A combination of clozapine and aripiprazole may be an effective therapeutic strategy for some schizophrenic patients, leading to a good response with respect to positive and negative symptoms without the occurrence of major side effects.

5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement.

BACKGROUND: Because of intratumoral heterogeneity, diffusely infiltrating gliomas that lack significant contrast enhancement on magnetic resonance imaging are prone to tissue sampling error. Subsequent histologic undergrading may delay adjuvant treatments. 5-Aminolevulinic acid (5-ALA) leads to accumulation of fluorescent porphyrins in malignant glioma tissue, and is currently used for resection of malignant gliomas. The aim of this study was to clarify whether 5-ALA might serve as marker for visualization of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement for precise intraoperative tissue sampling. METHODS: 5-ALA was administered in 17 patients with diffusely infiltrating gliomas with nonsignificant contrast enhancement. During glioma resection, positive fluorescence was noted by a modified neurosurgical microscope. Intraoperative topographic correlation of focal 5-ALA fluorescence with maximum (11)C-methionine positron emission tomography uptake (PET(max)) was performed. Multiple tissue samples were taken from areas of positive and/or negative 5-ALA fluorescence. Histopathological diagnosis was established according to World Health Organization (WHO) 2007 criteria. Cell proliferation was assessed for multiregional samples by MIB-1 labeling index (LI). RESULTS: Focal 5-ALA fluorescence was observed in 8 of 9 patients with WHO grade III diffusely infiltrating gliomas. All 8 of 8 WHO grade II diffusely infiltrating gliomas were 5-ALA negative. Focal 5-ALA fluorescence correlated topographically with PET(max) in all patients. MIB-1 LI was significantly higher in 5-ALA-positive than in nonfluorescent areas within a given tumor. CONCLUSIONS: The data indicate that 5-ALA is a promising marker for intraoperative visualization of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement. Unaffected by intraoperative brain shift, 5-ALA may increase the precision of tissue sampling during tumor resection for histopathological grading, and therefore optimize allocation of patients to adjuvant treatments.