Biomedical subjects

Claus Svarer

Publications and source records attributed to Claus Svarer.

14 recordsLinked to original sources

PubMed2006

Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach.

PURPOSE: To determine the reproducibility of measurements of brain 5-HT2A receptors with an [18F]altanserin PET bolus/infusion approach. Further, to estimate the sample size needed to detect regional differences between two groups and, finally, to evaluate how partial volume correction affects reproducibility and the required sample size. METHODS: For assessment of the variability, six subjects were investigated with [18F]altanserin PET twice, at an interval of less than 2 weeks. The sample size required to detect a 20% difference was estimated from [18F]altanserin PET studies in 84 healthy subjects. Regions of interest were automatically delineated on co-registered MR and PET images. RESULTS: In cortical brain regions with a high density of 5-HT2A receptors, the outcome parameter (binding potential, BP1) showed high reproducibility, with a median difference between the two group measurements of 6% (range 5-12%), whereas in regions with a low receptor density, BP1 reproducibility was lower, with a median difference of 17% (range 11-39%). Partial volume correction reduced the variability in the sample considerably. The sample size required to detect a 20% difference in brain regions with high receptor density is approximately 27, whereas for low receptor binding regions the required sample size is substantially higher. CONCLUSION: This study demonstrates that [18F]altanserin PET with a bolus/infusion design has very low variability, particularly in larger brain regions with high 5-HT2A receptor density. Moreover, partial volume correction considerably reduces the sample size required to detect regional changes between groups.

Adolescent↗

PubMed2006

Reproducibility of [123I]PE2I binding to dopamine transporters with SPECT.

PURPOSE: The iodinated cocaine derivative [(123)I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with SPECT. Recently, a bolus/infusion (B/I) protocol for [(123)I]PE2I measurements of DAT density was established [Pinborg LH et al. J Nucl Med 2005;46:1119-271]. The aims of this study were, firstly, to evaluate the test-retest variability using the B/I protocol and, secondly, to evaluate the B/I approach in a new group of healthy subjects using two outcome parameters, BP(1) (C(ROI)/C(plasma)) and BP(2) (C(ROI)/C(REF)). METHODS: Seven healthy subjects were subjected to [(123)I]PE2I SPECT scanning twice. For both studies, the two outcome parameters BP(1) and BP(2) were calculated based on two different methods for region of interest (ROI) delineation, namely manual delineation and probability map-based automatic delineation with MRI co-registration. RESULTS: With manual delineation, striatal test-retest variability (absolute difference between first and second scan as a percentage of the mean) of BP(1) and BP(2) was 13.9% (range 1.8-35.7%) and 4.1% (range 0.5-9.7%) respectively. The probability map-based automatic delineation resulted in striatal test-retest variability of 17.2% (range 4.3-40.5%) and 5.2% (range 0.1-10.9%) respectively. The B/I approach provided stable brain activity from 120 to 180 min post injection in both high- and low-count regions with a mean % change/hour in striatal BP(2) of 10.6. CONCLUSION: [(123)I]PE2I SPECT with the B/I approach yields a highly reproducible measure of striatal dopamine transporter binding. The appropriateness of a B/I protocol with a B/I ratio of 2.7 h (i.e. with a bolus worth 2.7 h of infusion) was confirmed in an independent sample of healthy subjects.

Adult↗

PubMed2006

Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender.

BACKGROUND: The aim of the study was to examine extrastriatal dopamine D(2/3) receptor binding and psychopathology in schizophrenic patients, and to relate binding potential (BP) values to psychopathology. METHODS: Twenty-five drug-naive schizophrenic patients and 20 healthy controls were examined with single-photon emission computerized tomography (SPECT) using the D(2/3)-receptor ligand [123I]epidepride. RESULTS: In the hitherto largest study on extrastriatal D(2/3) receptors we detected a significant correlation between frontal D(2/3) BP values and positive schizophrenic symptoms in the larger group of male schizophrenic patients, higher frontal BP values in male (n = 17) compared to female (n = 8) patients, and - in accordance with this - significantly fewer positive schizophrenic symptoms in the female patients. No significant differences in BP values were observed between patients and controls; the patients, however, had significantly higher BP in the right compared to the left thalamus, whereas no significant hemispheric imbalances were observed in the healthy subjects. CONCLUSIONS: The present data are the first to confirm a significant correlation between frontal D(2/3) receptor BP values and positive symptoms in male schizophrenic patients. They are in agreement with the hypothesis that frontal D(2/3) receptor activity is significant for positive psychotic symptoms. Additionally, the data support a thalamic hemispheric imbalance in schizophrenia.

Adult↗

PubMed2006

Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome.

Experimental and clinical data have suggested that abnormalities in the serotonergic neurotransmissions in frontal-subcortical circuits are involved in Tourette's syndrome. To test the hypothesis that the brain's 5-HT2A receptor binding is increased in patients with Tourette's syndrome, PET imaging was performed. Twenty adults with Tourette's syndrome and 20 healthy control subjects were investigated with PET-[18F]altanserin using a bolus-infusion protocol. Regions of interest were delineated automatically on co-registered MRI images, and partial volume-corrected binding parameters were extracted from the PET images. Comparison between control subjects and Tourette's syndrome patients showed increased specific [18F]altanserin binding, not only in the a-priori selected brain regions hypothesized to be involved in Tourette's syndrome, but also post-hoc analysis showed a global up-regulation when testing for a overall difference with a randomization test (p<0.03). Increased 5-HT2A receptor binding was found not only in regions closely related to subcortical regions in patients with Tourette's syndrome, but also in most other brain regions. Our data suggest that the serotonergic transmitter system is pathophysiologically involved in Tourette's syndrome and that a clinical trial with 5-HT2A receptor antagonists may be justified.

Adolescent↗

PubMed2005

Patients with obsessive-compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei.

The pharmacological efficacy of serotonergic-acting drugs suggest that patients with obsessive-compulsive disorder (OCD) may have alterations in their cerebral serotonergic (5-HT) receptor system, and previous neuroimaging studies of OCD patients have shown abnormalities in several fronto-subcortical regions. In this study we investigated cerebral 5-HT(2A) receptor binding in 15 untreated OCD patients and in 15 age- and gender-matched healthy volunteers by magnetic resonance imaging and [(18)F]altanserin positron emission tomography (PET). Eleven of the patients were rescanned with PET after receiving treatment with a selective serotonin reuptake inhibitor (SSRI). The distribution volumes of specific tracer binding (DV(3)') were calculated for 12 brain regions, and comparisons were made between: (1) healthy volunteers vs. untreated OCD patients, (2) healthy volunteers vs. treated OCD patients, and (3) OCD patients before and during treatment. When comparing the distribution volume for specific fronto-subcortical brain regions, significantly higher values were recorded in the caudate nuclei in OCD patients (DV(3)': 0.24+/-0.14) compared to the healthy control group (DV(3)': 0.15+/-0.13) (p<0.05, Wilcoxon matched-pairs test). This difference between groups was not present after treatment with SSRIs. There was no correlation between the severity of OCD symptoms and 5-HT(2A )receptor binding. An increase in 5-HT(2A) receptor binding is found in the caudate nuclei of untreated patients with OCD. The up-regulation in 5-HT(2A) receptors might be compensatory for a lack of serotonin in the feedback loop between the thalamus and orbito-frontal cortex, the caudate nuclei, and the globus pallidus.

Adolescent↗

PubMed2005

Quantification of 123I-PE2I binding to dopamine transporter with SPECT after bolus and bolus/infusion.

UNLABELLED: The aim of the present study was to describe a method combining easy implementation in a clinical setting with accuracy and precision in quantification of 123I-labeled N-(3-iodoprop-(2E)-enyl)-2beta-carboxymethoxy-3beta-(4'-methylphenyl)nortropane (PE2I) binding to brain dopamine transporter. METHODS: Five healthy subjects (mean age, 50 y; range, 40-68 y) were studied twice. In the first experiment, dynamic SPECT data and arterial plasma input curves obtained after 123I-PE2I bolus injection were assessed using Logan, kinetic, transient equilibrium, and peak equilibrium analyses. Accurate and precise determination of BP1 (binding potential times the free fraction in the metabolite-corrected plasma compartment) and BP2 (binding potential times the free fraction in the intracerebral nonspecifically bound compartment) was achieved using Logan analysis and kinetic analysis, with a total study time of 90 min. In the second experiment, (123)I-PE2I was administrated as a combined bolus and constant infusion. The bolus was equivalent to 2.7 h of constant infusion. RESULTS: The bolus-to-infusion ratio of 2.7 h was based on the average terminal clearance rate from plasma in the bolus experiments. Steady state was attained in brain and plasma within 2 h, and time-activity curves remained constant for another 2 h. Even when an average bolus-to-infusion ratio was used, the striatal BP1 and BP2 values calculated with kinetic analysis (BP1 = 21.1 +/- 1.1; BP2 = 4.1 +/- 0.4) did not significantly differ from those calculated with bolus/infusion analysis (BP1 = 21.0 +/- 1.2; BP2 = 4.3 +/- 0.3). Computer simulations confirmed that a 2-fold difference in terminal clearance rate from plasma translates into only a 10% difference in BP1 and BP2 calculated from 120 to 180 min after tracer administration. CONCLUSION: The bolus/infusion approach allows accurate and precise quantification of 123I-PE2I binding to dopamine transporter and is easily implemented in a clinical setting.

Adult↗

PubMed2004

MR-based automatic delineation of volumes of interest in human brain PET images using probability maps.

The purpose of this study was to develop and validate an observer-independent approach for automatic generation of volume-of-interest (VOI) brain templates to be used in emission tomography studies of the brain. The method utilizes a VOI probability map created on the basis of a database of several subjects' MR-images, where VOI sets have been defined manually. High-resolution structural MR-images and 5-HT(2A) receptor binding PET-images (in terms of (18)F-altanserin binding) from 10 healthy volunteers and 10 patients with mild cognitive impairment were included for the analysis. A template including 35 VOIs was manually delineated on the subjects' MR images. Through a warping algorithm template VOI sets defined from each individual were transferred to the other subjects MR-images and the voxel overlap was compared to the VOI set specifically drawn for that particular individual. Comparisons were also made for the VOI templates 5-HT(2A) receptor binding values. It was shown that when the generated VOI set is based on more than one template VOI set, delineation of VOIs is better reproduced and shows less variation as compared both to transfer of a single set of template VOIs as well as manual delineation of the VOI set. The approach was also shown to work equally well in individuals with pronounced cerebral atrophy. Probability-map-based automatic delineation of VOIs is a fast, objective, reproducible, and safe way to assess regional brain values from PET or SPECT scans. In addition, the method applies well in elderly subjects, even in the presence of pronounced cerebral atrophy.

Aged↗

PubMed2004

Cluster analysis in kinetic modelling of the brain: a noninvasive alternative to arterial sampling.

In emission tomography, quantification of brain tracer uptake, metabolism or binding requires knowledge of the cerebral input function. Traditionally, this is achieved with arterial blood sampling. We propose a noninvasive alternative via the use of a blood vessel time-activity curve (TAC) extracted directly from dynamic positron emission tomography (PET) scans by cluster analysis. Five healthy subjects were injected with the 5HT(2A)-receptor ligand [(18)F]-altanserin and blood samples were subsequently taken from the radial artery and cubital vein. Eight regions-of-interest (ROI) TACs were extracted from the PET data set. Hierarchical K-means cluster analysis was performed on the PET time series to extract a cerebral vasculature ROI. The number of clusters was varied from K = 1 to 10 for the second of the two-stage method. Determination of the correct number of clusters was performed by the 'within-variance' measure and by 3D visual inspection of the homogeneity of the determined clusters. The cluster-determined input curve was then used in Logan plot analysis and compared with the arterial and venous blood samples, and additionally with one of the currently used alternatives to arterial blood sampling, the Simplified Reference Tissue Model (SRTM) and Logan analysis with cerebellar TAC as an input. There was a good agreement (P < 0.05) between the values of Distribution Volume (DV) obtained from the K-means-clustered input function and those from the arterial blood samples. This work acts as a proof-of-principle that the use of cluster analysis on a PET data set could obviate the requirement for arterial cannulation when determining the input function for kinetic modelling of ligand binding, and that this may be a superior approach as compared to the other noninvasive alternatives.

Adult↗

PubMed2004

A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables.

This study presents the results of an analysis of 5-hydroxytryptamine (5-HT)(2A) receptors in 52 healthy subjects. Thirty men and twenty-two women aged between 21 and 79 years were investigated with magnetic resonance imaging (MRI) and [(18)F]-altanserin positron emission tomography (PET). The distribution volumes of specific tracer binding (DV(3)') was calculated for 15 brain regions using either cerebellum or pons as reference regions and correlations between DV(3)' and physiological and demographic variables were made. The regional distribution of [(18)F]-altanserin binding in the healthy human brain was in agreement with existing in vitro post-mortem human 5-HT(2A) data. Apart from nonspecific cerebellar binding (DV(2)), there was no gender difference in 5-HT(2A) binding. A positive correlation between cerebellar binding and age was observed and negative correlations between age and DV(3)' were found in all cortical regions, except occipital cortex, corresponding to a decrease in DV(3)' of 6% or 4% per decade with cerebellum or pons as reference regions, respectively. In several temporal and frontal cortical regions, positive correlations were found between body mass index (BMI) and DV(3)'. Our findings provide a resource to aid design of clinical studies of the 5-HT(2A) receptors. [(18)F]-altanserin binding appears to be unaffected by gender, but the effects of ageing must be considered for clinical studies. The correlations between different cortical regions' 5-HT(2A) binding and BMI should be explored in future studies.

Adult↗

PubMed2004

Integrated software for the analysis of brain PET/SPECT studies with partial-volume-effect correction.

UNLABELLED: We present software for integrated analysis of brain PET studies and coregistered segmented MRI that couples a module for automated placement of regions of interest (ROI) with 4 alternative methods for partial-volume-effect correction (PVEc). The accuracy and precision of these methods have been measured using 4 simulated (18)F-FDG PET studies with increasing degrees of atrophy. METHODS: The software allows the application of a set of labels, defined a priori in the Talairach space, to segmented and coregistered MRI. Resulting ROIs are then transferred onto the PET study, and corresponding values are corrected according to the 4 PVEc techniques under investigation, providing corresponding corrected values. To evaluate the PVEc techniques, the software was applied to 4 simulated (18)F-FDG PET studies, introducing increasingly larger experimental errors, including errors in coregistration (0- to 6-pixel misregistration), segmentation (-13.7% to 14.1% gray matter [GM] volume change) and resolution estimate errors (-16.9% to 26.8% full-width-at-half-maximum mismatch). RESULTS: Even in the absence of segmentation and coregistration errors, uncorrected PET values showed -37.6% GM underestimation and 91.7% WM overestimation. Voxel-based correction only for the loss of GM activity as a result of spill-out onto extraparenchymal tissues left a residual underestimation of GM values (-21.2%). Application of the method that took into account both spill-in and spill-out effects between any possible pair of ROIs (R-PVEc) and of the voxel-based method that corrects also for the WM activity derived from R-PVEC (mMG-PVEc) provided an accuracy above 96%. The coefficient of variation of the GM ROIs, a measure of the imprecision of the GM concentration estimates, was 8.5% for uncorrected PET data and decreased with PVEc, reaching 6.0% for mMG-PVEc. Coregistration errors appeared to be the major determinant of the imprecision. CONCLUSION: Coupling of automated ROI placement and PVEc provides a tool for integrated analysis of brain PET/MRI data, which allows a recovery of true GM ROI values, with a high degree of accuracy when R-PVEc or mMG-PVEc is used. Among the 4 tested PVEc methods, R-PVEc showed the greatest accuracy and is suitable when corrected images are not specifically needed. Otherwise, if corrected images are desired, the mMG-PVEc method appears the most adequate, showing a similar accuracy.

Brain↗

PubMed2003

Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach.

The aim of the present study is to describe and validate a method for accurate quantification of 5-hydroxytryptamine (5-HT)(2A) receptors using [18F]altanserin-positron emission tomography (PET) and the bolus/infusion approach. A bolus/infusion ratio of 1.75 h aimed at attaining rapid steady state in blood and brain was predicted from previous bolus studies performed in our laboratory. The infusion schedule was tested in normal subjects (n = 10) using dynamic PET and frequent plasma sampling for 6 h. Steady state was attained in brain and plasma within 2 h, and time-activity curves remained constant for another 3 h. To represent free and nonspecifically bound [18F]altanserin and its radiolabeled metabolites only, cerebellum must show no displacement in 5-HT(2A) displacement studies. To validate this, saturating doses of cold ketanserin were administered and it was found that specific binding of [18F]altanserin decreased uniformly to the level of the cerebellum and no change in the cerebellar time-activity curve was found after ketanserin administration. A shorter experimental setup was tested in a second group (n = 20) including patients with neuropsychiatric disorders. Dynamic PET (five frames of 8 minutes each) and venous blood sampling at midscan time started 2 h after [18F]altanserin administration. The mean percentage rate of change per hour in the outcome parameter, DV(3)', was low (mean -0.3% h-1; range -7.3-7.2% h-1) and no correlation of DV(3)' versus time was demonstrated. It is concluded that 5-HT(2A) receptor studies can be conducted within 2 h of [18F]altanserin infusion, yielding reliable results.

Adult↗

PubMed2002

[The working brain--how does it look like?].

Numerous brain functions, such as awareness of surroundings, control of movements, thoughts, and memory have always been a kind of mystery, which has provoked human curiosity and thus inspired research in many areas. The present paper gives an overview on imaging research of the human brain's functions. The historical progress is briefly reviewed with the emphasis on major Danish contributions. The major methods of mapping brain functions and their biological basis are mentioned. These methods are positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). They are highly technological and generate enormous amounts of data. Thus, data analysis will per se be a research area in brain imaging. Finally, several examples of the authors' results on functional activation are dealt with. These examples aim to illustrate the research area and its contribution to our increased knowledge of the working brain.

Acoustic Stimulation↗

PubMed2002

Quantification of [(123)I]PE2I binding to dopamine transporters with SPET.

The iodinated cocaine derivative [(123)I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with single-photon emission tomography (SPET). The aim of the present study was to describe a method for accurate quantification of binding data following a bolus injection of [(123)I]PE2I. Six healthy subjects (age 51+/-24 years) underwent xenon-133 SPET for quantification of regional CBF and [(123)I]PE2I SPET for quantification of DAT binding. rCBFs were within normal limits in all subjects. Fitting data to a two-tissue compartment model resulted in striatal K(1) values of 0.39+/-0.08 ml ml(-1) min(-1), equal to a first-pass extraction fraction of 0.72+/-0.13. Distribution volumes (DVs) were calculated using compartment analysis, area under the curve analysis and Logan analysis. Logan analysis is preferred since stable DV values were already obtained 120 min after [(123)I]PE2I injection. Mean striatal DV was 37.9+/-9.6 ml ml(-1) and mean occipital cortex DV was 5.5+/-0.7 ml ml(-1). In the absence of local pathology in a reference tissue, Logan analysis without blood sampling is an attractive method for accurate quantification of striatal [(123)I]PE2I binding. The distribution volume ratio (DVR) (6.6+/-1.4) was in good agreement with the DVR calculated with blood (6.7+/-1.4).

Area Under Curve↗

PubMed2002

Cluster analysis of activity-time series in motor learning.

Neuroimaging studies of learning focus on brain areas where the activity changes as a function of time. To circumvent the difficult problem of model selection, we used a data-driven analytic tool, cluster analysis, which extracts representative temporal and spatial patterns from the voxel-time series. The optimal number of clusters was chosen using a cross-validated likelihood method, which highlights the clustering pattern that generalizes best over the subjects. Data were acquired with PET at different time points during practice of a visuomotor task. The results from cluster analysis show practice-related activity in a fronto-parieto-cerebellar network, in agreement with previous studies of motor learning. These voxels were separated from a group of voxels showing an unspecific time-effect and another group of voxels, whose activation was an artifact from smoothing.

Adult↗