Rolf Larisch - Academia.edu (original) (raw)
Papers by Rolf Larisch
Nuclear medicine communications, 2006
Dopamine transporters are the target of psychostimulants used for treatment of attention-deficit/... more Dopamine transporters are the target of psychostimulants used for treatment of attention-deficit/hyperactivity disorder (ADHD). Therefore, the present study aimed to evaluate striatal dopamine transporter density in adult patients with ADHD. Twenty patients (11 female, nine male; mean age 35+/-7 years) and 20 control subjects (11 female, nine male, mean age 32 +/- 8 years) were examined with SPECT using the specific radiotracer 123I-FP-CIT. The ratio of striatal to cortical radioactivity concentration was used for semiquantitative evaluation of dopamine transporter binding potential (V3''). There was a significant influence of age (P < 0.001) and a trend towards an influence of gender (P = 0.053) on V3''. An ANCOVA with these covariates showed a slightly higher V3'' in the patients than in the control subjects (4.24 +/- 0.48 vs. 4.03 +/- 0.56; P = 0.02). This study provides further in-vivo evidence for an involvement of the dopamine transporter in ADHD. Ho...
2008 IEEE Nuclear Science Symposium Conference Record, 2008
In this study, we assess the impact of the reference tissue (frontal cortex, parietal cortex, cer... more In this study, we assess the impact of the reference tissue (frontal cortex, parietal cortex, cerebellum) on the magnitude of the binding potential obtained for the D2 receptor ligands [18F]N-methyl-benperidol and [123I]iodobenzamide in the rat striatum using dedicated small animal PET (“TierPET”), small animal SPECT (“TierSPECT”) or a conventional dual-head SPECT camera upgraded with multipinhole-collimators (“HiSPECT”). With all 3 cameras
The Open Nuclear Medicine Journal, 2009
Reviews in the Neurosciences, 2000
Dopaminergic synaptic function may be assessed either at the presynaptic terminal or at the posts... more Dopaminergic synaptic function may be assessed either at the presynaptic terminal or at the postsynaptic binding sites using molecular in vivo imaging methods. Apart from the density of binding sites, parameters such as alterations in dopamine synthesis, dopamine storage or dopamine release can be quantified either by application of specific radiotracers or by assessing the competition between the exogenous radioligand and endogenous dopamine. The performance of animal studies allows the induction of specific short-term or long-term synaptic conditions via pharmacological challenges or infliction of neurotoxic lesions. Therefore, small laboratory animals such as rats and mice have become invaluable models for a variety of human disorders. This article gives an overview of those small animal studies which have been performed so far on dopaminergic neurotransmission using in vivo imaging methods, with a special focus on the relevance of findings within the functional entity of the dopaminergic synapse. Taken together, in vivo investigations on animal models of Parkinson&amp;amp;amp;amp;amp;#39;s disease showed decreases of dopamine storage, dopamine release and dopamine transporter binding, no alterations of dopamine synthesis and DA release, and either increases or no alterations of D2 receptor binding, while in vivo investigations of animal models of Huntington&amp;amp;amp;amp;amp;#39;s disease. showed decreases of DAT and D1 receptor binding. For D2 receptor binding, both decreases and increases have been reported, dependent on the radioligand employed. Substances of abuse, such as alcohol, amphetamine and methylphenidate, led to an increase of dopamine release in striatal regions. This held for the acute application of substances to both healthy animals and animal models of drug abuse. Findings also showed that chronic application of cocaine induced long-term reductions of both D1 and D2 receptor binding, which disappeared after several weeks of withdrawal. Finally, preliminary results yielded the first evidence that acute pplication of haloperidol might induce a reduction of dopamine transporter binding, indicating an enhancement of dopamine release into the synaptic cleft. It is remarkable to what degree the findings obtained with small animal imaging devices correspond to the results of clinical and experimental studies on humans. This agreement underlines the validity of small animal imaging methods and demonstrates the feasibility of further investigations on animal models of human diseases.
Hormone and Metabolic Research, 2004
Previous studies on hypothyroid subjects have indicated serious psychiatric symptoms affecting th... more Previous studies on hypothyroid subjects have indicated serious psychiatric symptoms affecting the patients' quality of life. The present prospective cross-sectional study's aim was to examine these symptoms in thyroid patients with different functional states. A total of 254 patients (age: 56 +/- 14 years [mean +/- standard deviation], 181 female, 73 male) referred to a hospital for radioiodine treatment of hyperthyroidism or for follow-up of differentiated thyroid cancer, respectively, were included. All patients underwent the twelve-item general health questionnaire, which is an instrument for detecting mood disturbances. Euthyroid and hyperthyroid patients did not differ significantly in their general health questionnaire score (11 +/- 5 vs. 11 +/- 7), nor did subclinical hyperthyroid (11 +/- 6) or subclinical hypothyroid subjects (12 +/- 5). In contrast, hypothyroid patients showed a significantly higher mean score (17 +/- 7, p < 0.001, ANOVA). Binary logistic regression revealed that hypothyroidism increases age and gender-adjusted risk for critical mood deterioration by seven-fold. Thus, hypothyroidism represents a widely underestimated functional condition that may severely affect mental health.
European Journal of Endocrinology, 2010
The present study re-evaluates the inverse log TSH-free thyroxine (fT(4)) relationship, which has... more The present study re-evaluates the inverse log TSH-free thyroxine (fT(4)) relationship, which has generally been assumed to characterize the thyroid pituitary hypothalamic feedback regulation in thyroid function. The correlation between fT(4) and TSH was analyzed in two data sets from differing time periods involving 3223 and 6605 patients referred for thyroid testing, representing the whole range of thyroid functions from hypothyroidism to hyperthyroidism. We found that the data do not support a linear log TSH-fT(4) relationship; instead, the correlation&amp;amp;amp;#39;s gradient varies with thyroid function. As a consequence, an alternate model, based on the error function, was introduced. When directly comparing the models by means of curve fitting, using F-test and Akaike criteria, the alternate model results in a significantly better fit. The model was verified in the independent second set of data. Subgroup analysis of untreated patients added further proof to the non-linear model. We propose a refined non-linear model to describe the relationship between TSH and fT(4). It implies that TSH response to a deviating fT(4) value may not be log-linear, but may be disproportionally related to the extent of the deviation from an optimum set point. A better understanding of the complex nature of the TSH-fT(4) relationship may further the development of more precise clinical models and aid in better defining subclinical states of thyroid dysfunction. Also, it may encourage other biological interrelations to be reconsidered in the wake of advanced measurement techniques and more powerful computerized statistical procedures.
European Archives of Psychiatry and Clinical Neuroscience, 2011
Central nervous system (CNS) monoamine deficits have been linked to a number of pathological cond... more Central nervous system (CNS) monoamine deficits have been linked to a number of pathological conditions such as major depressive disorder. Individual biological variations in 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) might account for the variation in responses of neurotransmitter systems observed after the administration of clomipramine. The prolactin response to clomipramine has been widely used to assess CNS functioning. This open label study investigates the prolactin response induced by clomipramine in the plasma of healthy volunteers and whether it is related to changes in monoamine metabolites. The effects of clomipramine challenge on prolactin, 5-HIAA, HVA and MHPG were measured in 12 healthy volunteers. Samples were drawn directly before and 50 min after clomipramine infusion. A statistically significant increase in serum prolactin concentrations was measured in women 50 min after CMI infusion, but not in men. We found no significant increases in the serum monoamine metabolite concentrations 50 min after CMI infusion. Changes in HVA and 5-HIAA correlated statistically significantly and positively with the amount of prolactin release in the whole sample. Furthermore, positive correlations were found between ∆(50-0 min) 5-HIAA and ∆(50-0 min) HVA, although we did not find a correlation between ∆(50-0 min) prolactin and ∆(50-0 min) MHPG after clomipramine challenge. The pronounced prolactin release in healthy adult women might indicate a higher physiological sensitivity. Correlations between intra-individual changes in HVA, 5-HIAA and serum prolactin might indicate a central nervous effect of clomipramine on monoamine turnover. We conclude that monoamine changes in relation to prolactin response after clomipramine challenge may be suitable for characterizing the relationship between central serotonergic and dopaminergic function.
Endocrine Connections, 2015
Objective: Several influences modulate biochemical responses to weight-adjusted 28 levothyroxine ... more Objective: Several influences modulate biochemical responses to weight-adjusted 28 levothyroxine (L-T4) replacement dose. We conducted a secondary analysis of the 29 relationship of L-T4 dose to TSH and FT3, using a prospective observational study 30 examining the interacting equilibria between thyroid parameters. 31
Nuklearmedizin
The characteristics of 5HT2 receptor binding were investigated in major depression in vivo using ... more The characteristics of 5HT2 receptor binding were investigated in major depression in vivo using positron emission tomography and the radioligand F-18-altanserin. Twelve patients from families with high loading of depression living in a geographically restricted region were examined and compared with normal control subjects. At the time of the PET measurement all patients were remitted; in some of them remission was sustained by antidepressive medication. Binding potential was assessed by Logan's graphical analysis method. The binding of F-18-altanserin was about 38% lower in patients than in healthy controls (p < 0.001). A multiple regression analysis revealed that this difference was mainly induced by depression rather than by medication. The data suggest that 5HT2 receptors are altered in depression. We present evidence for a reduction of the receptor density, which might be usable as trait marker of subjects susceptible for depressive illness.
NeuroImage, 1999
Pharmacologically induced dopamine release can influence the postsynaptic receptor binding of dop... more Pharmacologically induced dopamine release can influence the postsynaptic receptor binding of dopaminergic radioligands. This effect has recently been described using in vivo imaging methods and has been attributed to competition of radiotracers with the endogenous ligand. The present study examines the effect of a motor activation task on dopamine release and the consequences of this release on the binding of the selective D 2 receptor ligand 123 I-iodobenzamide (IBZM) to striatal dopamine D 2 receptors. Eight subjects were asked to write a text beginning immediately before IBZM injection and continuing for 30 min thereafter. Eighteen other subjects remained in a supine resting state during this period and served as a control group. All subjects were right handed. We hypothesized that the writing task would lead to an increase of dopamine release. The increased competition of the endogenous ligand with IBZM should lead to a decreased postsynaptic IBZM binding in the experimental group. Images were acquired and reconstructed identically and anatomically normalized to a computerized brain atlas. Regions of interest were drawn covering the striatum and three different reference regions. Ratios of striatal-to-reference-tissue radioactivity accumulation were calculated as semi-quantitative estimates of D 2 receptor binding potential. This decreased bilaterally, although right-sided significantly more than left, regardless of the choice of reference region. These data show that writing with the right hand compared to a supine resting state leads to a decrease of striatal IBZM accumulation. According to our primary hypothesis this reflects dopamine release.
Thyroid, 2002
The aim of this retrospective study was to investigate the value of positron emission tomography ... more The aim of this retrospective study was to investigate the value of positron emission tomography (PET) with 2-18 fluor-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 5 13) PET was initiated because of an elevated thyroglobulin (Tg) level whereas in subgroup B (n 5 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 truepositive 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 followup of HTC.
![Research paper thumbnail of Dopamine D2 receptor binding before and after treatment of major depression measured by [123I]IBZM SPECT](https://attachments.academia-assets.com/53979464/thumbnails/1.jpg)
](Psychiatry Research: Neuroimaging, 1999
Neuroscience Letters, 1999
The present study addresses the effect of motivation on cerebral activity using functional magnet... more The present study addresses the effect of motivation on cerebral activity using functional magnetic resonance imaging. Five healthy volunteers performed a dichotic listening task in two sets of three trials during which high or low levels of achievement motivation were introduced. They were told that the ®rst set would be used for calculation of intellectual capacity (high achievement motivation) and the second set for scanner calibration (neutral motivation). In three volunteers, high compared with neutral motivation produced activation in the right prefrontal cortex and the dorsal cingulate. We conclude that motivational effects may lead to signi®cant activations and should be controlled in future cognitive imaging studies. We present preliminary evidence that right prefrontal and dorsal cingulate regions might be involved in motivational processes. q
NeuroImage, 1997
The dopaminergic system is a candidate neurotransmitter system thought to be involved in the path... more 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-D 2 receptors were characterized in 13 patients with major depression using the dopamine-D 2 receptor antagonist iodobenzamide and single photon emission tomography. Dopamine receptor binding was assessed twice, before and during serotonin reuptake inhibition. An increase in dopamine-D 2 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-D 2 receptor binding correlated significantly with clinical recovery from depression as assessed with the Hamilton depression scale (r 5 0.59 for right and left striatum respectively, P F 0.05; r 5 0.79 for the anterior cingulate gyrus, P F 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-D 2 receptors may constitute a central role in this domain. r 1997 Academic Press
European Archives of Psychiatry and Clinical Neuroscience, 2011
Central nervous system (CNS) monoamine deficits have been linked to a number of pathological cond... more Central nervous system (CNS) monoamine deficits have been linked to a number of pathological conditions such as major depressive disorder. Individual biological variations in 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) might account for the variation in responses of neurotransmitter systems observed after the administration of clomipramine. The prolactin response to clomipramine has been widely used to assess CNS functioning. This open label study investigates the prolactin response induced by clomipramine in the plasma of healthy volunteers and whether it is related to changes in monoamine metabolites. The effects of clomipramine challenge on prolactin, 5-HIAA, HVA and MHPG were measured in 12 healthy volunteers. Samples were drawn directly before and 50 min after clomipramine infusion. A statistically significant increase in serum prolactin concentrations was measured in women 50 min after CMI infusion, but not in men. We found no significant increases in the serum monoamine metabolite concentrations 50 min after CMI infusion. Changes in HVA and 5-HIAA correlated statistically significantly and positively with the amount of prolactin release in the whole sample. Furthermore, positive correlations were found between ∆(50-0 min) 5-HIAA and ∆(50-0 min) HVA, although we did not find a correlation between ∆(50-0 min) prolactin and ∆(50-0 min) MHPG after clomipramine challenge. The pronounced prolactin release in healthy adult women might indicate a higher physiological sensitivity. Correlations between intra-individual changes in HVA, 5-HIAA and serum prolactin might indicate a central nervous effect of clomipramine on monoamine turnover. We conclude that monoamine changes in relation to prolactin response after clomipramine challenge may be suitable for characterizing the relationship between central serotonergic and dopaminergic function.
Der Nervenarzt, 1998
Andere im Bereich der Neuromedizin eingesetzte Radiopharmaka sind Rezeptorliganden, wie beispiels... more Andere im Bereich der Neuromedizin eingesetzte Radiopharmaka sind Rezeptorliganden, wie beispielsweise das C-11-Racloprid, das sich an den Dopamin-D 2 -Rezeptor bindet, und das C-11-Flumazenil, das sich an die die Benzodiazepin-Bindungsstelle des GABA A -Rezeptors setzt. Weiterhin läßt sich mit F-18-Dopa auch die präsynaptische Dopaminsynthese mit der PET erfassen. Im Bereich der Neuromedizin ist die PET mit zahlreichen Radiopharmaka primär zu Forschungszwecken eingesetzt worden. Die hierbei gewonnenen Erkenntnisse, die Weiterentwicklung der Kameratechnologie und die zunehmende Verbreitung der PET haben jedoch auch dazu geführt, daß PET zunehmend Eingang in die Diagnostik findet.
Depression and Anxiety, 2009
Background: Blunting of prolactin response after serotonergic stimulation during a major depressi... more Background: Blunting of prolactin response after serotonergic stimulation during a major depressive episode has been described by several investigators. In this study, the neuroendocrine responses to clomipramine were assessed in remitted patients suffering from hereditary depression. Methods: Twenty remitted patients from 11 large families with multigenerational, multiple cases of major affective disorder (bipolar disorder n = 15, recurrent depression n=5, according DSM-IV) and 12 healthy relatives were investigated. After intravenous application of 12.5 mg of the serotonin re-uptake inhibitor clomipramine, serum prolactin and cortisol levels were analysed. Results: Patients and comparison group did not differ significantly with respect to age, baseline prolactin and cortisol concentrations. A gender effect was found in an exploratory analysis for prolactin but not for cortisol and therefore the data for prolactin were analysed seperately. After clomipramine infusion, the increase of cortisol was significantly lower in patients than in the comparison group (P = .046). For prolactin, this effect could be found in the male (P = .012) as well as in the female (P = .007) subsample. Conclusions: These results suggest that blunted prolactin and cortisol responses to serotonergic stimulation are characteristic for remitted depressive patients with previous episodes of major affective disorders. Depression and Anxiety 26:E111-E119, 2009.
![Research paper thumbnail of Influence of synaptic serotonin level on [18F]altanserin binding to 5HT2 receptors in man](https://attachments.academia-assets.com/53979461/thumbnails/1.jpg)
](Behavioural Brain Research, 2003
The feasibility of in vivo serotonin 5HT 2 receptor binding measurement using [ 18 F]altanserin a... more The feasibility of in vivo serotonin 5HT 2 receptor binding measurement using [ 18 F]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 Logan's 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.
Therapeutic Advances in Endocrinology and Metabolism, 2017
Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to ... more Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to differentiate contributions of FT4 and FT3 in controlling pituitary thyroid stimulating hormone (TSH) secretion.
Methods: We retrospectively assessed the relationships between TSH and thyroid hormones in 319 patients with thyroid carcinoma through 2914 visits on various LT4 doses during follow-up for 5.5 years (median, IQR 4.2, 6.9). We also associated patient complaints with the relationships.
Results: Under varying dose requirements (median 1.84 μg/kg, IQR 1.62, 2.11), patients reached TSH targets below 0.4, 0.1 or 0.01 mIU/l at 73%, 54% and 27% of visits. While intercept, slope and fit of linearity of the relationships between lnTSH and FT4/FT3 varied between individuals, gender, age, LT4 dose and deiodinase activity influenced the relationships in the cohort (all p < 0.001). Deiodinase activity impaired by LT4 dose significantly affected the lnTSH–FT4 relationship. Dose increase and reduced conversion efficiency displaced FT3–TSH equilibria. In LT4-treated patients, FT4 and FT3 contributed on average 52% versus 38%, and by interaction 10% towards TSH suppression. Symptomatic presentations (11%) accompanied reduced FT3 concentrations (–0.23 pmol/l, p = 0.001) adjusted for gender, age and BMI, their relationships being shifted towards higher TSH values at comparable FT3/FT4 levels.
Conclusions: Variation in deiodinase activity and resulting FT3 levels shape the TSH–FT4 relationship in LT4-treated athyreotic patients, suggesting cascade control of pituitary TSH production by the two hormones. Consequently, measurement of FT3 and calculation of conversion efficiency may identify patients with impaired biochemistry and a resulting lack of symptomatic control.
Nuclear medicine communications, 2006
Dopamine transporters are the target of psychostimulants used for treatment of attention-deficit/... more Dopamine transporters are the target of psychostimulants used for treatment of attention-deficit/hyperactivity disorder (ADHD). Therefore, the present study aimed to evaluate striatal dopamine transporter density in adult patients with ADHD. Twenty patients (11 female, nine male; mean age 35+/-7 years) and 20 control subjects (11 female, nine male, mean age 32 +/- 8 years) were examined with SPECT using the specific radiotracer 123I-FP-CIT. The ratio of striatal to cortical radioactivity concentration was used for semiquantitative evaluation of dopamine transporter binding potential (V3''). There was a significant influence of age (P < 0.001) and a trend towards an influence of gender (P = 0.053) on V3''. An ANCOVA with these covariates showed a slightly higher V3'' in the patients than in the control subjects (4.24 +/- 0.48 vs. 4.03 +/- 0.56; P = 0.02). This study provides further in-vivo evidence for an involvement of the dopamine transporter in ADHD. Ho...
2008 IEEE Nuclear Science Symposium Conference Record, 2008
In this study, we assess the impact of the reference tissue (frontal cortex, parietal cortex, cer... more In this study, we assess the impact of the reference tissue (frontal cortex, parietal cortex, cerebellum) on the magnitude of the binding potential obtained for the D2 receptor ligands [18F]N-methyl-benperidol and [123I]iodobenzamide in the rat striatum using dedicated small animal PET (“TierPET”), small animal SPECT (“TierSPECT”) or a conventional dual-head SPECT camera upgraded with multipinhole-collimators (“HiSPECT”). With all 3 cameras
The Open Nuclear Medicine Journal, 2009
Reviews in the Neurosciences, 2000
Dopaminergic synaptic function may be assessed either at the presynaptic terminal or at the posts... more Dopaminergic synaptic function may be assessed either at the presynaptic terminal or at the postsynaptic binding sites using molecular in vivo imaging methods. Apart from the density of binding sites, parameters such as alterations in dopamine synthesis, dopamine storage or dopamine release can be quantified either by application of specific radiotracers or by assessing the competition between the exogenous radioligand and endogenous dopamine. The performance of animal studies allows the induction of specific short-term or long-term synaptic conditions via pharmacological challenges or infliction of neurotoxic lesions. Therefore, small laboratory animals such as rats and mice have become invaluable models for a variety of human disorders. This article gives an overview of those small animal studies which have been performed so far on dopaminergic neurotransmission using in vivo imaging methods, with a special focus on the relevance of findings within the functional entity of the dopaminergic synapse. Taken together, in vivo investigations on animal models of Parkinson&amp;amp;amp;amp;amp;#39;s disease showed decreases of dopamine storage, dopamine release and dopamine transporter binding, no alterations of dopamine synthesis and DA release, and either increases or no alterations of D2 receptor binding, while in vivo investigations of animal models of Huntington&amp;amp;amp;amp;amp;#39;s disease. showed decreases of DAT and D1 receptor binding. For D2 receptor binding, both decreases and increases have been reported, dependent on the radioligand employed. Substances of abuse, such as alcohol, amphetamine and methylphenidate, led to an increase of dopamine release in striatal regions. This held for the acute application of substances to both healthy animals and animal models of drug abuse. Findings also showed that chronic application of cocaine induced long-term reductions of both D1 and D2 receptor binding, which disappeared after several weeks of withdrawal. Finally, preliminary results yielded the first evidence that acute pplication of haloperidol might induce a reduction of dopamine transporter binding, indicating an enhancement of dopamine release into the synaptic cleft. It is remarkable to what degree the findings obtained with small animal imaging devices correspond to the results of clinical and experimental studies on humans. This agreement underlines the validity of small animal imaging methods and demonstrates the feasibility of further investigations on animal models of human diseases.
Hormone and Metabolic Research, 2004
Previous studies on hypothyroid subjects have indicated serious psychiatric symptoms affecting th... more Previous studies on hypothyroid subjects have indicated serious psychiatric symptoms affecting the patients' quality of life. The present prospective cross-sectional study's aim was to examine these symptoms in thyroid patients with different functional states. A total of 254 patients (age: 56 +/- 14 years [mean +/- standard deviation], 181 female, 73 male) referred to a hospital for radioiodine treatment of hyperthyroidism or for follow-up of differentiated thyroid cancer, respectively, were included. All patients underwent the twelve-item general health questionnaire, which is an instrument for detecting mood disturbances. Euthyroid and hyperthyroid patients did not differ significantly in their general health questionnaire score (11 +/- 5 vs. 11 +/- 7), nor did subclinical hyperthyroid (11 +/- 6) or subclinical hypothyroid subjects (12 +/- 5). In contrast, hypothyroid patients showed a significantly higher mean score (17 +/- 7, p < 0.001, ANOVA). Binary logistic regression revealed that hypothyroidism increases age and gender-adjusted risk for critical mood deterioration by seven-fold. Thus, hypothyroidism represents a widely underestimated functional condition that may severely affect mental health.
European Journal of Endocrinology, 2010
The present study re-evaluates the inverse log TSH-free thyroxine (fT(4)) relationship, which has... more The present study re-evaluates the inverse log TSH-free thyroxine (fT(4)) relationship, which has generally been assumed to characterize the thyroid pituitary hypothalamic feedback regulation in thyroid function. The correlation between fT(4) and TSH was analyzed in two data sets from differing time periods involving 3223 and 6605 patients referred for thyroid testing, representing the whole range of thyroid functions from hypothyroidism to hyperthyroidism. We found that the data do not support a linear log TSH-fT(4) relationship; instead, the correlation&amp;amp;amp;#39;s gradient varies with thyroid function. As a consequence, an alternate model, based on the error function, was introduced. When directly comparing the models by means of curve fitting, using F-test and Akaike criteria, the alternate model results in a significantly better fit. The model was verified in the independent second set of data. Subgroup analysis of untreated patients added further proof to the non-linear model. We propose a refined non-linear model to describe the relationship between TSH and fT(4). It implies that TSH response to a deviating fT(4) value may not be log-linear, but may be disproportionally related to the extent of the deviation from an optimum set point. A better understanding of the complex nature of the TSH-fT(4) relationship may further the development of more precise clinical models and aid in better defining subclinical states of thyroid dysfunction. Also, it may encourage other biological interrelations to be reconsidered in the wake of advanced measurement techniques and more powerful computerized statistical procedures.
European Archives of Psychiatry and Clinical Neuroscience, 2011
Central nervous system (CNS) monoamine deficits have been linked to a number of pathological cond... more Central nervous system (CNS) monoamine deficits have been linked to a number of pathological conditions such as major depressive disorder. Individual biological variations in 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) might account for the variation in responses of neurotransmitter systems observed after the administration of clomipramine. The prolactin response to clomipramine has been widely used to assess CNS functioning. This open label study investigates the prolactin response induced by clomipramine in the plasma of healthy volunteers and whether it is related to changes in monoamine metabolites. The effects of clomipramine challenge on prolactin, 5-HIAA, HVA and MHPG were measured in 12 healthy volunteers. Samples were drawn directly before and 50 min after clomipramine infusion. A statistically significant increase in serum prolactin concentrations was measured in women 50 min after CMI infusion, but not in men. We found no significant increases in the serum monoamine metabolite concentrations 50 min after CMI infusion. Changes in HVA and 5-HIAA correlated statistically significantly and positively with the amount of prolactin release in the whole sample. Furthermore, positive correlations were found between ∆(50-0 min) 5-HIAA and ∆(50-0 min) HVA, although we did not find a correlation between ∆(50-0 min) prolactin and ∆(50-0 min) MHPG after clomipramine challenge. The pronounced prolactin release in healthy adult women might indicate a higher physiological sensitivity. Correlations between intra-individual changes in HVA, 5-HIAA and serum prolactin might indicate a central nervous effect of clomipramine on monoamine turnover. We conclude that monoamine changes in relation to prolactin response after clomipramine challenge may be suitable for characterizing the relationship between central serotonergic and dopaminergic function.
Endocrine Connections, 2015
Objective: Several influences modulate biochemical responses to weight-adjusted 28 levothyroxine ... more Objective: Several influences modulate biochemical responses to weight-adjusted 28 levothyroxine (L-T4) replacement dose. We conducted a secondary analysis of the 29 relationship of L-T4 dose to TSH and FT3, using a prospective observational study 30 examining the interacting equilibria between thyroid parameters. 31
Nuklearmedizin
The characteristics of 5HT2 receptor binding were investigated in major depression in vivo using ... more The characteristics of 5HT2 receptor binding were investigated in major depression in vivo using positron emission tomography and the radioligand F-18-altanserin. Twelve patients from families with high loading of depression living in a geographically restricted region were examined and compared with normal control subjects. At the time of the PET measurement all patients were remitted; in some of them remission was sustained by antidepressive medication. Binding potential was assessed by Logan's graphical analysis method. The binding of F-18-altanserin was about 38% lower in patients than in healthy controls (p < 0.001). A multiple regression analysis revealed that this difference was mainly induced by depression rather than by medication. The data suggest that 5HT2 receptors are altered in depression. We present evidence for a reduction of the receptor density, which might be usable as trait marker of subjects susceptible for depressive illness.
NeuroImage, 1999
Pharmacologically induced dopamine release can influence the postsynaptic receptor binding of dop... more Pharmacologically induced dopamine release can influence the postsynaptic receptor binding of dopaminergic radioligands. This effect has recently been described using in vivo imaging methods and has been attributed to competition of radiotracers with the endogenous ligand. The present study examines the effect of a motor activation task on dopamine release and the consequences of this release on the binding of the selective D 2 receptor ligand 123 I-iodobenzamide (IBZM) to striatal dopamine D 2 receptors. Eight subjects were asked to write a text beginning immediately before IBZM injection and continuing for 30 min thereafter. Eighteen other subjects remained in a supine resting state during this period and served as a control group. All subjects were right handed. We hypothesized that the writing task would lead to an increase of dopamine release. The increased competition of the endogenous ligand with IBZM should lead to a decreased postsynaptic IBZM binding in the experimental group. Images were acquired and reconstructed identically and anatomically normalized to a computerized brain atlas. Regions of interest were drawn covering the striatum and three different reference regions. Ratios of striatal-to-reference-tissue radioactivity accumulation were calculated as semi-quantitative estimates of D 2 receptor binding potential. This decreased bilaterally, although right-sided significantly more than left, regardless of the choice of reference region. These data show that writing with the right hand compared to a supine resting state leads to a decrease of striatal IBZM accumulation. According to our primary hypothesis this reflects dopamine release.
Thyroid, 2002
The aim of this retrospective study was to investigate the value of positron emission tomography ... more The aim of this retrospective study was to investigate the value of positron emission tomography (PET) with 2-18 fluor-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 5 13) PET was initiated because of an elevated thyroglobulin (Tg) level whereas in subgroup B (n 5 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 truepositive 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 followup of HTC.
Psychiatry Research: Neuroimaging, 1999
Neuroscience Letters, 1999
The present study addresses the effect of motivation on cerebral activity using functional magnet... more The present study addresses the effect of motivation on cerebral activity using functional magnetic resonance imaging. Five healthy volunteers performed a dichotic listening task in two sets of three trials during which high or low levels of achievement motivation were introduced. They were told that the ®rst set would be used for calculation of intellectual capacity (high achievement motivation) and the second set for scanner calibration (neutral motivation). In three volunteers, high compared with neutral motivation produced activation in the right prefrontal cortex and the dorsal cingulate. We conclude that motivational effects may lead to signi®cant activations and should be controlled in future cognitive imaging studies. We present preliminary evidence that right prefrontal and dorsal cingulate regions might be involved in motivational processes. q
NeuroImage, 1997
The dopaminergic system is a candidate neurotransmitter system thought to be involved in the path... more 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-D 2 receptors were characterized in 13 patients with major depression using the dopamine-D 2 receptor antagonist iodobenzamide and single photon emission tomography. Dopamine receptor binding was assessed twice, before and during serotonin reuptake inhibition. An increase in dopamine-D 2 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-D 2 receptor binding correlated significantly with clinical recovery from depression as assessed with the Hamilton depression scale (r 5 0.59 for right and left striatum respectively, P F 0.05; r 5 0.79 for the anterior cingulate gyrus, P F 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-D 2 receptors may constitute a central role in this domain. r 1997 Academic Press
European Archives of Psychiatry and Clinical Neuroscience, 2011
Central nervous system (CNS) monoamine deficits have been linked to a number of pathological cond... more Central nervous system (CNS) monoamine deficits have been linked to a number of pathological conditions such as major depressive disorder. Individual biological variations in 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) might account for the variation in responses of neurotransmitter systems observed after the administration of clomipramine. The prolactin response to clomipramine has been widely used to assess CNS functioning. This open label study investigates the prolactin response induced by clomipramine in the plasma of healthy volunteers and whether it is related to changes in monoamine metabolites. The effects of clomipramine challenge on prolactin, 5-HIAA, HVA and MHPG were measured in 12 healthy volunteers. Samples were drawn directly before and 50 min after clomipramine infusion. A statistically significant increase in serum prolactin concentrations was measured in women 50 min after CMI infusion, but not in men. We found no significant increases in the serum monoamine metabolite concentrations 50 min after CMI infusion. Changes in HVA and 5-HIAA correlated statistically significantly and positively with the amount of prolactin release in the whole sample. Furthermore, positive correlations were found between ∆(50-0 min) 5-HIAA and ∆(50-0 min) HVA, although we did not find a correlation between ∆(50-0 min) prolactin and ∆(50-0 min) MHPG after clomipramine challenge. The pronounced prolactin release in healthy adult women might indicate a higher physiological sensitivity. Correlations between intra-individual changes in HVA, 5-HIAA and serum prolactin might indicate a central nervous effect of clomipramine on monoamine turnover. We conclude that monoamine changes in relation to prolactin response after clomipramine challenge may be suitable for characterizing the relationship between central serotonergic and dopaminergic function.
Der Nervenarzt, 1998
Andere im Bereich der Neuromedizin eingesetzte Radiopharmaka sind Rezeptorliganden, wie beispiels... more Andere im Bereich der Neuromedizin eingesetzte Radiopharmaka sind Rezeptorliganden, wie beispielsweise das C-11-Racloprid, das sich an den Dopamin-D 2 -Rezeptor bindet, und das C-11-Flumazenil, das sich an die die Benzodiazepin-Bindungsstelle des GABA A -Rezeptors setzt. Weiterhin läßt sich mit F-18-Dopa auch die präsynaptische Dopaminsynthese mit der PET erfassen. Im Bereich der Neuromedizin ist die PET mit zahlreichen Radiopharmaka primär zu Forschungszwecken eingesetzt worden. Die hierbei gewonnenen Erkenntnisse, die Weiterentwicklung der Kameratechnologie und die zunehmende Verbreitung der PET haben jedoch auch dazu geführt, daß PET zunehmend Eingang in die Diagnostik findet.
Depression and Anxiety, 2009
Background: Blunting of prolactin response after serotonergic stimulation during a major depressi... more Background: Blunting of prolactin response after serotonergic stimulation during a major depressive episode has been described by several investigators. In this study, the neuroendocrine responses to clomipramine were assessed in remitted patients suffering from hereditary depression. Methods: Twenty remitted patients from 11 large families with multigenerational, multiple cases of major affective disorder (bipolar disorder n = 15, recurrent depression n=5, according DSM-IV) and 12 healthy relatives were investigated. After intravenous application of 12.5 mg of the serotonin re-uptake inhibitor clomipramine, serum prolactin and cortisol levels were analysed. Results: Patients and comparison group did not differ significantly with respect to age, baseline prolactin and cortisol concentrations. A gender effect was found in an exploratory analysis for prolactin but not for cortisol and therefore the data for prolactin were analysed seperately. After clomipramine infusion, the increase of cortisol was significantly lower in patients than in the comparison group (P = .046). For prolactin, this effect could be found in the male (P = .012) as well as in the female (P = .007) subsample. Conclusions: These results suggest that blunted prolactin and cortisol responses to serotonergic stimulation are characteristic for remitted depressive patients with previous episodes of major affective disorders. Depression and Anxiety 26:E111-E119, 2009.
Behavioural Brain Research, 2003
The feasibility of in vivo serotonin 5HT 2 receptor binding measurement using [ 18 F]altanserin a... more The feasibility of in vivo serotonin 5HT 2 receptor binding measurement using [ 18 F]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 Logan's 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.
Therapeutic Advances in Endocrinology and Metabolism, 2017
Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to ... more Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to differentiate contributions of FT4 and FT3 in controlling pituitary thyroid stimulating hormone (TSH) secretion.
Methods: We retrospectively assessed the relationships between TSH and thyroid hormones in 319 patients with thyroid carcinoma through 2914 visits on various LT4 doses during follow-up for 5.5 years (median, IQR 4.2, 6.9). We also associated patient complaints with the relationships.
Results: Under varying dose requirements (median 1.84 μg/kg, IQR 1.62, 2.11), patients reached TSH targets below 0.4, 0.1 or 0.01 mIU/l at 73%, 54% and 27% of visits. While intercept, slope and fit of linearity of the relationships between lnTSH and FT4/FT3 varied between individuals, gender, age, LT4 dose and deiodinase activity influenced the relationships in the cohort (all p < 0.001). Deiodinase activity impaired by LT4 dose significantly affected the lnTSH–FT4 relationship. Dose increase and reduced conversion efficiency displaced FT3–TSH equilibria. In LT4-treated patients, FT4 and FT3 contributed on average 52% versus 38%, and by interaction 10% towards TSH suppression. Symptomatic presentations (11%) accompanied reduced FT3 concentrations (–0.23 pmol/l, p = 0.001) adjusted for gender, age and BMI, their relationships being shifted towards higher TSH values at comparable FT3/FT4 levels.
Conclusions: Variation in deiodinase activity and resulting FT3 levels shape the TSH–FT4 relationship in LT4-treated athyreotic patients, suggesting cascade control of pituitary TSH production by the two hormones. Consequently, measurement of FT3 and calculation of conversion efficiency may identify patients with impaired biochemistry and a resulting lack of symptomatic control.