Henning Vosberg

Dopamine D2 receptor binding before and after treatment of major depression measured by [123I]IBZM SPECT

Fifteen patients fulfilling DSM-IV criteria for major depression were investigated with the specific dopamine D2 receptor antagonist [123I]iodobenzamide (IBZM). Two single photon emission computed tomography (SPECT) examinations were performed before and after 6 weeks of treatment with a selective serotonin re-uptake inhibitor (SSRI). Striatal D2 receptor binding was calculated and normalized to the cerebellum. In a non-psychiatric control group (n = 17), which was investigated once with [123I]IBZM and SPECT, striatal IBZM binding decreased significantly with age (0.092 per decade). The age-dependent correlation was lower in subjects with major depression and did not reach statistical significance. There was no significant difference in mean IBZM binding between depressives and control subjects. Age-corrected baseline IBZM binding in the striatum was significantly lower in treatment responders than in depressed non-responders and control subjects. Furthermore, in the depressive group there was a significant linear correlation between treatment response and change of D2 receptor binding during treatment in the basal ganglia. IBZM binding increased in treatment responders and decreased in non-responders. In accordance with animal studies, the results suggest an association between changes in the dopaminergic system and treatment response in major depression.

Staging of Pelvic Lymph Nodes in Neoplasms of the Bladder and Prostate by Positron Emission Tomography with 2-[18F]-2-Deoxy-D-Glucose

Objectives: The aim of this study was to evaluate whether pelvic lymph node metastases in patients with neoplasms of the bladder or prostate can be detected applying positron emission tomography with 2-[18F]-2-deoxy-D-glucose (FDG-PET). Methods: Eight patients with bladder cancer and 17 patients with prostate cancer were examined with FDG–PET before pelvic lymph node dissection. Results of PET were then compared to histology of pelvic lymph nodes obtained at surgery. Results: Lymph node metastases were detected by histopathological examination in 3 patients with bladder cancer and in 6 patients with prostate cancer. At the sites with histologically proven metastases, increased FDG uptake suspicious of metastatic disease was found in 2/3 and 4/6 patients, respectively. The smallest detected metastasis was a micrometastasis with a diameter of 0.9 cm. In 3 additional patients who all had histopathologically proven micrometastases (∅ ≤0.5 cm), FDG uptake was within the normal range. No false-positive results were obtained. Conclusions: These results suggest that FDG-PET may be a valuable diagnostic tool in the staging of pelvic lymph nodes in bladder and prostate cancer.

In VivoEvidence for the Involvement of Dopamine-D2Receptors in Striatum and Anterior Cingulate Gyrus in Major Depression

The dopaminergic system is a candidate neurotransmitter system thought to be involved in the pathogenesis of depression. This study addresses the issue whether the antidepressant efficacy of serotonin reuptake inhibition is related to changes in the cerebral dopaminergic system. Cerebral dopamine-D2 receptors were characterized in 13 patients with major depression using the dopamine-D2 receptor antagonist iodobenzamide and single photon emission tomography. Dopamine receptor binding was assessed twice, before and during serotonin reuptake inhibition. An increase in dopamine-D2 receptor binding during serotonin reuptake inhibition was found in striatum and anterior cingulate gyrus in treatment responders, but not in nonresponders. The increase in dopamine-D2 receptor binding correlated significantly with clinical recovery from depression as assessed with the Hamilton depression scale (r = 0.59 for right and left striatum respectively, P < 0.05; r = 0.79 for the anterior cingulate gyrus, P < 0.05 after Bonferroni correction). Qualitatively similar correlations were observed in the precentral gyrus, the medial frontal gyrus, the inferior frontal gyrus, and the frontal part of the opercular gyrus, but these correlations failed to reach statistical significance after correction for the effects of multiple testing. No such correlations were found in the superior frontal gyrus, the orbitofrontal gyrus, the gyrus rectus, the superior parietal gyrus, or the superior temporal gyrus. The data strengthen the concept that the striatum and the anterior cingulate gyrus are involved in mood regulation. Dopamine-D2 receptors may constitute a central role in this domain.

Implication of 2-18fluor-2-deoxyglucose positron emission tomography in the follow-up of Hürthle cell thyroid cancer.

The aim of this retrospective study was to investigate the value of positron emission tomography (PET) with 2-18fluor-2-deoxy-glucose (FDG) in the follow-up of Hürthle cell thyroid cancer (HTC), a rare variant of thyroid malignancies. FDG-PET studies were performed in 17 patients with HTC. In subgroup A (n = 13) PET was initiated because of an elevated thyroglobulin (Tg) level whereas in subgroup B (n = 4) the study was performed to evaluate suspect findings of morphologic imaging while Tg remained undetectable. Pathologically increased FDG uptake was found in all patients of subgroup A. In 10 studies, PET results were proven as true-positive either by surgery or by morphologic imaging. One study was false-positive. Final evaluation was not possible in two cases. In subgroup B, PET was true-negative in three and false-positive in one patient. For the detection of recurrent HTC by means of FDG-PET a meta-analysis including data of a multicenter study revealed an overall sensitivity of 92%, a specificity of 80%, a positive predictive value of 92%, and a negative predictive value of 80% while the accuracy was 89%. This study supports the efficiency of FDG-PET in the follow-up of HTC.

4.5 tesla magnetic field reduces range of high-energy positrons-potential implications for positron emission tomography

We have theoretically and experimentally investigated the extent to which homogeneous magnetic fields up to 7 Tesla reduce the spatial distance positrons travel before annihilation (positron range). Computer simulations of a noncoincident detector design using a Monte Carlo algorithm calculated the positron range as a function of positron energy and magnetic field strength. The simulation predicted improvements in resolution, defined as full-width at half-maximum (FWBM) of the line-spread function (LSP) for a magnetic field strength up to 7 Tesla: negligible for F-18, from 3.35 mm to 2.73 mm for Ga-68 and from 3.66 mm to 2.68 mm for Rb-82. Also a substantial noise suppression was observed, described by the full-width at tenth-maximum (FWTM) for higher positron energies. The experimental approach confirmed an improvement in resolution for Ga-68 from 3.54 mm at 0 Tesla to 2.99 mm FWHM at 4.5 Tesla and practically no improvement for F-18 (2.97 mm at 0 Tesla and 2.95 mm at 4.5 Tesla). It is concluded that the simulation model is appropriate and that a homogeneous static magnetic field of 4.5 Tesla reduces the range of high-energy positrons to an extent that may improve spatial resolution in positron emission tomography.

Positron-emission tomography with 18F-2-fluoro-2-deoxy-D-glucose (18FDG-PET) in the diagnosis of retroperitoneal lymph-node metastases from testicular tumors

SummaryIn 1991, this prospectively designed study was started to assess the potentials of positron emission tomography with 18FDG in the diagnostic workup for the detection of lymph node metastases in testicular cancer, since there were no data available concerning this subject at this time. In 54 patients (27 patients with pure seminoma, 27 patients with non-seminomatous tumors) 18FDG-PET results were compared with the findings obtained with abdominal computed tomography, serum level of tumor markers (AFP, β -HCG), and the histopathological findings after primary or post-chemotherapy retroperitoneal lymph node dissection. In 21 patients with pure seminoma (clinical stage I according to the Lugano classification) 18FDG-PET results were identical with those of the abdominal computed tomography, so PET does not add relevant informations in this group of patients. In 7 patients presenting with non-seminomatous testicular cancer (stage I), PET was not able to detect the existing micrometastases in 4 patients. In 1/7 case PET examination showed a suspicious focal lesion, this lymph node had 2 micrometastases within inflammatory changes. In 1/7 patient 18FDG-PET definitely revealed metastatic lesions, while the CT scans where judged to be unobtrusive and tumor marker levels were within the normal range. In the 4 patients with pure seminomas stage II B and II C (N = 6), that have undergone retroperitoneal lymph node dissection following chemotherapy, 18FDG-PET correctly predicted absence of tumor in 3 out of these 4, and in 1/4 patient the benign nature of a persistent large tumor after two cycles of polychemotherapy was correctly identified wich eventually turned out to be a ganglioneuroma. This lesion falsely was classified as malignant tumor with abdominal computed tomography, and in 2/4 patients post-chemotherapy residual retroperitoneal lesions in the CT scans could not be assessed exactly whether or not malignant tumor was present. In 20 patients presenting with non-seminomatous testicular cancer (stage II and III) 18FDG-PET was able to demonstrate therapeutic effects of chemotherapy by showing decreasing tracer activity in those regions, that had hypermetabolic foci prior to chemotherapy. It became evident in testicular cancer that there is a single entity which is not characterized by increased glucose metabolism, the mature teratoma. In lesions detected by abdominal computed tomography which do not present increased 18FDG uptake, mature teratoma as well as scar/necrosis or rare other tumors with normal glucose metabolism can be supposed, but additional characteristics based on different 18FDG uptake were not observed. In 1/20 case post-chemotherapy PET scan detected a hypermetabolic lesion, which was suspicious for metastatic spread, but in the histopathological examination this lesion was identified as inflammatory tissue reaction. Based on the data reported here in 18FDG-PET cannot be considered a standard diagnostic tool in the staging examinations in testicular cancer. It is of clinical relevance in patients who present residual tumor after chemotherapy. In this situation 18FDG-PET is helpful in deciding whether or not a residual mass post-chemotherapy contains active tumor. 18FDG-PET can not replace retroperitoneal lymph node dissection for staging purposes.ZusammenfassungDas Ziel dieser 1991 begonnenen prospektiven Studie war, die Bedeutung der Positronenemissionstomographie mit 18FDG bei der Diagnostik der Lymphknotenmetastasen von Hodentumoren zu untersuchen, da zu diesem Zeitpunkt keine Daten bezüglich dieser Fragestellung zur Verfügung standen. Es wird über 54 Patienten berichtet (27 Patienten mit reinem Seminom, 27 Patienten mit nichtseminomatösen Tumoren), bei denen die 18FDG-PET-Resultate mit den Befunden der abdominellen Computertomographie, den Werten für die Tumormarker (AFP, β -HCG) sowie den histopathologischen Befunden nach primärer oder post-chemotherapeutischer retroperitonealer Lymphknotendissektion verglichen wurden. Bei reinen Seminomen im klinischen Stadium I nach der Lugano-Klassifikation (N = 21) waren die 18FDG-PET-Ergebnisse identisch mit denen der Computertomographie, so daß das Verfahren bei dieser Patientengruppe keine zusätzlichen Informationen bringt. Bei Patienten mit nichtseminomatösen Tumoren im Stadium I (N = 7) wurden bei 4 Patienten die vorliegenden Mikrometastasen durch die PET nicht detektiert, bei 1/7 Patienten hat die PET-Messung einen suspekten Herd ergeben, es fanden sich 2 Mikrometastasen in einem zusätzlich entzündlich veränderten Lymphknoten. In 1/7 Fall hat die 18FDG-PET eindeutig Metastasen detektiert (Tumormarker und Computertomogramm waren unauffällig). Bei den reinen Seminomen der Stadien II B und II C (N = 6) hat 18FDG-PET nach Chemotherapie das tumorfreie Lymphknotendissektat (pN0) von den 4 operierten Patienten 3 mal richtig präoperativ erkannt und im vierten Fall einer persistierenden großen Raumforderung die benigne Eigenschaft der Läsion (Ganglioneurom) identifiziert. Computertomographisch wurde dieser Befund als maligne (falsch-positiv) eingestuft, und bei 2/4 Patienten konnten computertomographisch residuale Lymphknoten nach Chemotherapie nicht eindeutig klassifiziert werden. Bei 20 Patienten mit nicht-seminomatösen Tumoren (Stadien II und III) konnte mit 18FDG-PET der Einfluß der Chemotherapie durch Aktivitätsminderung in prätherapeutisch hypermetabolen Herden (Normalisierung bis auf Hintergrundniveau) dargestellt werden. Es gibt eine einzige maligne Ausprägung der Hodentumoren, das reife Teratom, welche keine vermehrte 18FDG-Aufnahme zeigt. Bei computertomographisch erkennbaren, in der PET aber unauffällig dargestellten Läsionen sind differentialdiagnostisch reifes Teratom, Narbengewebe und/oder Nekrose bzw. seltene andere Tumorarten ohne gesteigerten Glukosestoffwechsel in Erwägung zu ziehen, aber eindeutige Unterschiede der Traceraufnahme zur weiteren Differenzierung wurden nicht beobachtet. In 1/20 Fall lag in der PET postchemotherapeutisch ein hypermetaboler Herd, fälschlich als maligne eingestuft, vor, der entsprechende Lymphknoten zeigte histopathologisch entzündliche Veränderungen. 18FDG-PET ist nicht als Routine-Untersuchungsverfahren bei Hodentumoren anzusehen. Die sinnvollste Anwendung ist bei der Bewertung von post-chemotherapeutischen Residualtumoren gegeben, um eine Entscheidungshilfe bei der Indikationsstellung zur RLA/weiteren Chemotherapie zu sein, jedoch ist die RLA zum Staging der Lymphknoten durch den Einsatz der 18FDG-PET nicht zu ersetzen.

High resolution SPECT in small animal research.

Single Photon Emission Computed Tomography (SPECT) is a technique used to assess physiological and biochemical processes under in vivo conditions. SPECT generates tomographic images from blood flow, glucose metabolism and receptor characteristics using radioactively labelled substances. This paper reviews the state of the art of in vivo imaging of laboratory animals in modified human and dedicated animal SPECT scanners. SPECT cameras with special collimators currently reach spatial resolutions up to 1 mm and sensitivities of about 1000 cps/MBq, allowing observation of receptor activity concentration changes in the pico-mole range. The time resolution of such cameras strongly depends on the pharmacological behaviour of the tracer and can range from several minutes to hours. Within these limits the functional characterization of many processes is possible. SPECT also offers the possibility to set up dynamic study protocols and repeated measurements of the same animal. This technique reduces the need for sacrificing animals, as was commonly practiced before the development of animal cameras. Animal SPECT gives the opportunity to monitor physiological and biochemical processes in animals in vivo, without interfering with the system under observation, and may become a valuable adjunct to the instrumentation (autoradiography, in vitro methods) of animal research.

Influence of synaptic serotonin level on [18F]altanserin binding to 5HT2 receptors in man

The feasibility of in vivo serotonin 5HT(2) receptor binding measurement using [18F]altanserin as a radioligand has been well established. In this study, the postsynaptic receptor binding potential of this ligand was examined as a possible indicator of synaptic serotonin content after pharmacological challenge. Studies were performed in 11 subjects with a history of recurrent major depression. Six of them received serotonergic antidepressive treatment at the time of the experiment, the other five patients were untreated. Two PET measurements were carried out in each subject within 2 or 3 days. Before one of the measurements, 25 mg of the serotonin re-uptake inhibitor clomipramine were given intravenously, the other measurement was done without pharmacological challenge. The data were analyzed using non-linear least-square regression and Logans graphical method. In the whole group of subjects, binding potential and distribution volume of altanserin decreased following clomipramine challenge. The decrease was between 14 (P=0.03) and 23% (P=0.004). This effect was mainly seen in subjects not on antidepressive medication. Clomipramine challenge probably increased the synaptic serotonin level, which competed with altanserin leading to the lowered binding potential. The paradigm might, thus, be useful to estimate serotonin release in vivo. Pretreatment with serotonergic antidepressants reduces the effect of clomipramine.

Model identification and estimation of organ-function parameters using radioactive tracers and the impulse-response function

Examination of the input-output events in functioning organs by the use of the impulse-response function (IRF) for a radioactive tracer is gaining more and more ground in nuclear medicine. This study summarizes the development of deconvolution analysis, laying special stress on the ‘model-free’ approach. System linearity and time invariance are discussed, and means of eliminating noise in IRFs originating from the input and organ-time-activity curves are outlined. Typical IRFs are illustrated by flow diagrams, time-domain curves, and their representation by Laplace transforms. The cases of nondiffusible and diffusible tracers as well as parenchymally extracted and transported substances are discussed. Methods for the derivation of models and for the calculation of physiologically important parameters from theIRFs are suggested.

The utilization of Tc-99m-TBI as a myocardial perfusion agent in exercise studies: Comparison with Tl-201 thallous chloride and examination of its biodistribution in humans

Twenty-four patients were studied with both 201Tl-thallous chloride and 99mTc-TBI scintigraphy following exercise. Comparison of the two agents in detecting segmental myocardial ischemia and scar was made in 18 patients with evidence of coronary artery disease on 201Tl-thallous chloride scintigraphy. Agreement between the two studies was observed in 77% (125 of 162) of left ventricular segments, suggesting that 99mTc-TBI can be used as a myocardial perfusion agent. Limitations were related to early high background activity from lungs and liver. The high lung activity and early myocardial redistribution within the 1st hour contributed to the failure of 99mTc-TBI to detect 16 segmental defects seen in the immediate post-exercise thallous chloride scan. Persistently high liver activity additionally affected accurate interpretation in the left ventricular segments close to the diaphargm. Improvement in the accuracy of 99mTc-TBI stress studies might be achieved with tomographic imaging to reduce the problem of background activity or by the development of 99mTc-labeled isonitrile analogues with rapid lung and liver clearance.