Carin Muhr

Dopamine receptors in pituitary adenomas: PET visualization with 11C-N-methylspiperone.

Two patients with pituitary tumors were examined with positron emission tomography (PET) after intravenous administration of 11C-N-methylspiperone. In repeat studies the patients were given 1 mg of intravenous haloperidol prior to the administration of the radioligand to block the dopamine receptors. High uptakes of the radiolabeled ligand were seen in one of the tumors. With haloperidol pretreatment the uptake was lower, probably mainly showing the remaining unspecific binding. The most marked uptake and the largest effect of haloperidol pretreatment was seen in a patient with a hormonally active prolactinoma. Dopamine receptor binding in pituitary tumors can be demonstrated in vivo with PET, and quantification of this binding is possible using a compartmental model. This technique may be useful in improving our understanding of the variable response to medical treatment of prolactinomas with dopamine agonists as well as in the prediction of the effect of such treatment.

Rapid decrease in amino acid metabolism in prolactin-secreting pituitary adenomas after bromocriptine treatment: a PET study.

Four patients with prolactin-secreting pituitary adenomas were examined with positron emission tomography using L-[11C]methionine to monitor the effect of dopamine agonist treatment on the amino acid metabolism in the tumors. Within the first few hours after intramuscular injection of bromocriptine retard (50 mg) the amino acid metabolism decreased by 40%. Two of the patients were reexamined 7 and 9 days later and showed a 70% reduction in the metabolism of the adenomas. This metabolic effect was later accompanied by significant tumor shrinkage in all adenomas. It is suggested that bromocriptine has a general and rapid effect on the protein synthesis of the prolactin-secreting pituitary adenoma cells.

Malignant Prolactinoma with Multiple Intracranial Metastases Studied with Positron Emission Tomography

A rare case of a patient with multiple intracranial metastases from a prolactin-secreting pituitary neoplasm is described. At the age of 14 years, the patient had been operated on for a sellar tumor; he presented 12 years later with severe headache, at which time computed tomographic and magnetic resonance imaging scans revealed multiple intracranial metastases. Histopathology examination showed pituitary neoplastic cells with positive immunostaining for prolactin. The patient was investigated with positron emission tomography (PET) and dopamine D2-receptor binding, and the amino acid metabolism of the tumor was characterized in vivo. High dopamine D2-receptor binding and high amino acid metabolism were found in the tumor. The patient was subsequently treated with bromocriptine injections that resulted in a decrease in serum prolactin levels, decreased dopamine D2-receptor binding, reduced amino acid metabolism, and a reduction in tumor volume. This case demonstrates a beneficial effect of bromocriptine treatment in a patient with prolactinoma with multiple intracranial metastases. It also illustrates the great potential of PET in the in vivo characterization of the D2-binding and the high sensitivity of 11C-labeled L-methionine in the follow-up of treatment in patients with pituitary adenomas.

Mri of pituitary macroadenomas with reference to hormonal activity

SummaryIn 115 patients with pituitary macroadenomas, the findings on mid-field MRI were correlated with the hormonal activity of the tumours. Adenomas secreting growth hormone (GH), prolactin (PRL) and clinically nonsecretory adenomas were studied. Tumour size, invasiveness and signal intensity patterns were recorded. Relaxation times and ratios of signal intensity and proton density (relative to the corpus callosum) were analysed in areas of apparently solid tissue in a subgroup of 59 previously untreated patients. Invasiveness was more common in PRL-and GH-secreting adenomas than in the nonsecreting ones. Diffuse invasion of the base of the skull was most common in prolactinomas, and associated with a lower frequency of suprasellar tumour extension. In prolactinomas, a correlation was found between the maximum serum PRL level and tumour size. Haemorrhagic, cystic or necrotic areas were less common in GH-secreting tumours than in the other types. Haemorrhage was more common in prolactinomas than in nonsecreting tumours. MR parameters were similar in prolactinomas and nonsecreting adenomas, but indicated a smaller amount of water in GH-secreting tumours.

Positron Emission Tomography in Acromegaly and Other Pituitary Adenoma Patients

Background: Positron emission tomography (PET) is a well-recognized technique used in research, especially for intracranial studies, as well as for clinical practice, and has contributed to the fast development in neuroscience during the last decades. Procedures: We have used PET in pituitary tumors for in vivo characterization with respect to metabolism, 11C-L-methionine and 18F-fluorodeoxyglucose, receptor properties, 11C-N-methylspiperone and 11C-raclopride, and monoamine oxidase B enzyme content, 11C-L-deprenyl; further, for diagnosing and outlining the tumors in differential diagnostic perspectives and in the follow-up of treatment. Observations:11C-raclopride, a specific dopamine antagonist, demonstrated high amounts of dopamine D2 binding in prolactinomas and some growth hormone-secreting adenomas. There was a significant correlation between high amounts of D2 receptors and the positive treatment effect of dopamine agonist therapy. When 11C-L-methionine and 18F-fluorodeoxyglucose were used for metabolic mapping, the highest metabolic activity was found in the prolactinomas, which correlated well with the serum prolactin levels. The growth hormone adenomas also showed high metabolic rates. At treatment follow-up, a considerable decrease in 11C-L-methionine uptake was observed in all tumors that responded positively to the treatment and thus foretold that the medical treatment, both concerning dopamine agonist and somatostatin analogue, was effective. In this respect, PET was valuable to monitor treatment. PET was also shown valuable in differential diagnosing between pituitary adenomas, meningiomas and skull base neuromas. Conclusion: We have found PET to be highly valuable in the research and clinical handling of patients with a pituitary adenoma for in vivo tumor characterization.

Multimodal behavioral treatment of migraine: An Internet-administered, randomized, controlled trial

Abstract Introduction. Multimodal approaches in behavioral treatment have gained recent interest, with proven efficacy for migraine. The utility of the Internet has been demonstrated for behavioral treatment of headache disorders, but not specifically for migraine. The aim of the study was to develop and evaluate an Internet-based multimodal behavior treatment (MBT) program for migraine and to test hand massage treatment as an adjunct. Methods. Eighty-three adults, 58 women and 25 men, with at least two migraine attacks a month were recruited via advertisements. An MBT program aiming at improvements in life-style and stress coping was developed for this study and, together with a diary, adapted for use over the Internet. Participants were randomized to MBT with and without hand massage and to a control group, and were followed for 11 months. Questionnaires addressing issues of quality of life (PQ23) and depressive symptoms (MADRS-S) were used. Results. A 50%, or greater, reduction in migraine frequency was found in 40% and 42% of participants of the two groups receiving MBT (with and without hand massage, respectively), who statistically were significantly more improved than participants in the control group. No effect of hand massage was detected, and gender did not show any independent contribution to the effect in a multivariate analysis. Conclusions. MBT administered over the Internet appears feasible and effective in the treatment of migraine, but no effect of hand massage was found. For increased knowledge on long-term effects and the modes of action of the present MBT program, further studies are needed.

Stress in migraine: personality-dependent vulnerability, life events, and gender are of significance.

Abstract Background and aim. The individuals experiences of stress as well as constitutional factors, including high neuroticism and female gender, are known determinants for migraine. The present aim was to further elucidate factors of personality and stress, including life events, in relation to gender in migraine. Methods. A cross-sectional study was performed on 150 persons, 106 women and 44 men, suffering from at least two migraine attacks a month. All obtained a doctor-defined migraine diagnosis based on a structured face-to-face interview concerning their health situation and current and prior stress. All of them also answered validated questionnaires regarding personality traits (SSP), life events, and perceived ongoing stress. Results. The personality trait inventory showed high mean scores for stress susceptibility and low mean scores for aggressiveness and adventure seeking, both for women and for men, as well as high mean scores for psychic and somatic anxiety in women. Stress susceptibility, the overall most deviant trait, correlated strikingly with current level of stress in both sexes. In women, stress susceptibility also correlated strongly with experiences of negative life events. Tension-type headache, anxiety, and depression were approximately twice as prevalent in women compared to men. Conclusions. The present study confirms previous research, showing that stress is an important factor in migraine. Stress susceptibility, life events, and concomitant psychosomatic illnesses should be considered important when evaluating individuals with migraine, and gender aspects need to be taken into account.

Effects of prostaglandin and leukotriene inhibitors on the growth of human glioma spheroids.

Established cell-lines of human glioma origin were cultured as multicellular spheroids or as monolayers. Volume growth and 3H-thymidine labelling were analysed for the spheroids after continuous exposure to drugs interfering with the release of arachidonic acid and the production of prostaglandins and leukotrienes. Comparative measurements were made on monolayer cultures. The cyclo-oxygenase inhibitor indomethacin enhanced growth at intermediate concentrations (0.5-5.0 micrograms/ml) but reduced growth at 50 micrograms/ml. The dual cyclo-oxygenase and lipoxygenase inhibitor ketoprofen had a significant inhibitory effect on growth and cell proliferation of spheroids at high concentration (50 micrograms/ml). The weak lipoxygenase inhibitor NDGA (quinone-form) decreased growth whereas the strong lipoxygenase inhibitor NDGA (hydroquinone-form) did not reduce growth rate but significantly decreased cell proliferation. Quinacrine reduced the spheroid growth rate although dexamethasone had no effects. Thus, inhibitors of the arachidonic acid cascade had growth inhibitory effects in the spheroid tumour model as well as in cells cultured as monolayers.

Kinetics of four 11C-labelled enkephalin peptides in the brain, pituitary and plasma of Rhesus monkeys

The kinetics of four 11C-labelled enkephalin peptides: Tyr-Gly-Gly-Phe-Met (Met-enkephalin), Tyr-D-Met-Gly-Phe-Pro-NH2 [D-Met2,Pro5)-enkephalinamide), Tyr-D-Ala-Gly-Phe-Met-NH2 (DALA) and Tyr-D-Ala-D-Ala-Phe-Met-NH2 (TAAFM) all labelled at the methyl group of methionine was studied in the Rhesus monkey. After intravenous administration, the regional kinetics in the head, lungs, liver and kidneys were followed by means of positron emission tomography (PET). The total radioactivity in blood and urine was measured and the composition of 11C-labelled peptide fragments in plasma in vivo and in vitro was analysed by liquid chromatography. With PET, an increased radioactivity was observed in the brain and pituitary over the 60-90 min investigation period after i.v. injection of the peptides. The highest radioactivities were noted for Met-enkephalin, followed by DALA and D-Met2, Pro5-enkephalinamide, while very low radioactivities were found for TAAFM. The uptake of Met-enkephalin- and DALA-derived radioactivity was of the same order as has previously been shown for morphine in the brain and considerably higher than that of D-Met2,Pro5-enkephalinamide and TAAFM, respectively. A large fraction of the brain radioactivity derived from Met-enkephalin and DALA probably emanated from [11C]methionine as indicated by plasma and urine analysis. Met-Enkephalin was rapidly eliminated from plasma in vitro with an half-life of less than two minutes, whereas DALA was stable suggesting clearance by other tissues than plasma. In conclusion, both Met-enkephalin and DALA, were rapidly hydrolyzed in vivo to [11C]methionine. [11C]Methionine was probably taken up in the brain, as the radioactivity increased with time in different brain regions as measured with PET.D-Met2,Pro5-Enkephalinamide and TAAFM were virtually stable in vivo and at least part of the radioactivity observed in the brain may have represented the intact peptide.

Amino Acid Distribution and Metabolism in Pituitary Adenomas Using Positron Emission Tomography with D-[11C]Methionine and L-[11C]Methionine

Four patients with hormonally inactive pituitary adenomas were examined with positron emission tomography (PET) after injection, during different examinations, of L-[methyl-11C]methionine and D-[methyl-11C]methionine, respectively. After the rapid distribution phase, the enantiomer L-[11C]methionine, which is metabolically active, showed a considerable continuous irreversible trapping attributed to amino acid metabolism. The stereoisomer D-[11C]methionine, which does not participate in protein synthesis, showed a rapid distribution within the whole adenoma tissue, with a distribution space on the order of 100%. A minimal irreversible trapping was observed which could be explained by technical factors. It is concluded that PET using the two enantiomers allows a separation of passive distribution and metabolism, and that L-[11C]methionine can be used for in vivo quantitative studies of amino acid metabolism of pituitary adenomas.