C. Svarer

Reduced 5-HT2A receptor binding in patients with mild cognitive impairment

Previous studies of patients with Alzheimers disease (AD) have described reduced brain serotonin 2A (5-HT(2A)) receptor density. It is unclear whether this abnormality sets in early in the course of the disease and whether it is related to early cognitive and neuropsychiatric symptoms. We assessed cerebral 5-HT(2A) receptor binding in patients with mild cognitive impairment (MCI) and related 5-HT(2A) receptor binding to clinical symptoms. Sixteen patients with MCI of the amnestic type (mean age 73, mean MMSE 26.1) and 17 age and sex matched control subjects were studied with MRI and [(18)F]altanserin PET in a bolus-infusion approach. A significant global reduction of 20-30% in 5-HT(2A) binding (atrophy corrected) was found in most neocortical areas. Reduced 5-HT(2A) binding in the striatum correlated significantly with Neuropsychiatric Inventory depression and anxiety scores. We conclude that widespread reductions in 5-HT(2A) receptor binding were found in amnestic MCI, pointing at the presence of serotonergic dysfunction in prodromal AD. This may provide some of the pathophysiological background for the neuropsychiatric symptoms found in early AD.

Cerebral serotonin transporter binding is inversely related to body mass index

Overweight and obesity is a health threat of increasing concern and understanding the neurobiology behind obesity is instrumental to the development of effective treatment regimes. Serotonergic neurotransmission is critically involved in eating behaviour; cerebral level of serotonin (5-HT) in animal models is inversely related to food intake and body weight and some effective anti-obesity agents involve blockade of the serotonin transporter (SERT). We investigated in 60 healthy volunteers body mass index (BMI) and regional cerebral SERT binding as measured with [(11)C]DASB PET. In a linear regression model with adjustment for relevant covariates, we found that cortical and subcortical SERT binding was negatively correlated to BMI (-0.003 to -0.012 BP(ND) unit per kg/m(2)). Tobacco smoking and alcohol consumption did not affect cerebral SERT binding. Several effective anti-obesity drugs encompass blockade of the SERT; yet, our study is the first to demonstrate an abnormally decreased cerebral SERT binding in obese individuals. Whether the SERT has a direct role in the regulation of appetite and eating behaviour or whether the finding is due to a compensatory downregulation of SERT secondary to other dysfunction(s) in the serotonergic transmitter system, such as low baseline serotonin levels, remains to be established.

Frontal Dopamine D2/3 Receptor Binding in Drug-Naive First-Episode Schizophrenic Patients Correlates with Positive Psychotic Symptoms and Gender

BACKGROUNDnThe 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.nnnMETHODSnTwenty-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.nnnRESULTSnIn 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.nnnCONCLUSIONSnThe 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.

Design and regularization of neural networks: the optimal use of a validation set

We derive novel algorithms for estimation of regularization parameters and for optimization of neural net architectures based on a validation set. Regularisation parameters are estimated using an iterative gradient descent scheme. Architecture optimization is performed by approximative combinatorial search among the relevant subsets of an initial neural network architecture by employing a validation set based optimal brain damage/surgeon (OBD/OBS) or a mean field combinatorial optimization approach. Numerical results with linear models and feed-forward neural networks demonstrate the viability of the methods.

Regional brain volumes, diffusivity, and metabolite changes after electroconvulsive therapy for severe depression

To investigate the role of hippocampal plasticity in the antidepressant effect of electroconvulsive therapy (ECT).

Attenuation Correction for the HRRT PET-Scanner Using Transmission Scatter Correction and Total Variation Regularization

In the standard software for the Siemens high-resolution research tomograph (HRRT) positron emission tomography (PET) scanner the most commonly used segmentation in the μ-map reconstruction for human brain scans is maximum a posteriori for transmission (MAP-TR). Bias in the lower cerebellum and pons in HRRT brain images have been reported. The two main sources of the problem with MAP-TR are poor bone/soft tissue segmentation below the brain and overestimation of bone mass in the skull. Method: We developed the new transmission processing with total variation (TXTV) method that introduces scatter correction in the μ-map reconstruction and total variation filtering to the transmission processing. Results: Comparing MAP-TR and the new TXTV with gold standard CT-based attenuation correction, we found that TXTV has less bias as compared to MAP-TR. We also compared images acquired at the HRRT scanner using TXTV to the GE Advance scanner images and found high quantitative correspondence. TXTV has been used to reconstruct more than 4000 HRRT scans at seven different sites with no reports of biases. Conclusion: TXTV-based reconstruction is recommended for human brain scans on the HRRT.

Central 5-HT neurotransmission modulates weight loss following gastric bypass surgery in obese individuals.

The cerebral serotonin (5-HT) system shows distinct differences in obesity compared with the lean state. Here, it was investigated whether serotonergic neurotransmission in obesity is a stable trait or changes in association with weight loss induced by Roux-in-Y gastric bypass (RYGB) surgery. In vivo cerebral 5-HT2A receptor and 5-HT transporter binding was determined by positron emission tomography in 21 obese [four men; body mass index (BMI), 40.1 ± 4.1 kg/m2] and 10 lean (three men; BMI, 24.6 ± 1.5 kg/m2) individuals. Fourteen obese individuals were re-examined after RYGB surgery. First, it was confirmed that obese individuals have higher cerebral 5-HT2A receptor binding than lean individuals. Importantly, we found that higher presurgical 5-HT2A receptor binding predicted greater weight loss after RYGB and that the change in 5-HT2A receptor and 5-HT transporter binding correlated with weight loss after RYGB. The changes in the 5-HT neurotransmission before and after RYGB are in accordance with a model wherein the cerebral extracellular 5-HT level modulates the regulation of body weight. Our findings support that the cerebral 5-HT system contributes both to establish the obese condition and to regulate the body weight in response to RYGB.

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

PurposeQuantitative estimates of dopamine transporter availability, determined with [123I]FP-CIT SPECT, depend on the SPECT equipment, including both hardware and (reconstruction) software, which limits their use in multicentre research and clinical routine. This study tested a dedicated reconstruction algorithm for its ability to reduce camera-specific intersubject variability in [123I]FP-CIT SPECT. The secondary aim was to evaluate binding in whole brain (excluding striatum) as a reference for quantitative analysis.MethodsOf 73 healthy subjects from the European Normal Control Database of [123I]FP-CIT recruited at six centres, 70 aged between 20 and 82xa0years were included. SPECT images were reconstructed using the QSPECT software package which provides fully automated detection of the outer contour of the head, camera-specific correction for scatter and septal penetration by transmission-dependent convolution subtraction, iterative OSEM reconstruction including attenuation correction, and camera-specific “to kBq/ml” calibration. LINK and HERMES reconstruction were used for head-to-head comparison. The specific striatal [123I]FP-CIT binding ratio (SBR) was computed using the Southampton method with binding in the whole brain, occipital cortex or cerebellum as the reference. The correlation between SBR and age was used as the primary quality measure.ResultsThe fraction of SBR variability explained by age was highest (1) with QSPECT, independently of the reference region, and (2) with whole brain as the reference, independently of the reconstruction algorithm.ConclusionQSPECT reconstruction appears to be useful for reduction of camera-specific intersubject variability of [123I]FP-CIT SPECT in multisite and single-site multicamera settings. Whole brain excluding striatal binding as the reference provides more stable quantitative estimates than occipital or cerebellar binding.

Striatal D2/3 Binding Potential Values in Drug-Naïve First-Episode Schizophrenia Patients Correlate With Treatment Outcome

One of best validated findings in schizophrenia research is the association between blockade of dopamine D2 receptors and the effects of antipsychotics on positive psychotic symptoms. The aim of the present study was to examine correlations between baseline striatal D2/3 receptor binding potential (BPp) values and treatment outcome in a cohort of antipsychotic-naïve first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D2/3 receptor blockade and alterations of negative symptoms as well as functioning and subjective well-being. Twenty-eight antipsychotic-naïve schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [123I]iodobenzamide ([123I]-IBZM) was used to examine striatal D2/3 receptor BPp. Patients were examined before and after 6 weeks of treatment with the D2/3 receptor antagonist amisulpride. There was a significant negative correlation between striatal D2/3 receptor BPp at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed significantly lower baseline BPp in the responders. At follow-up, the patients demonstrated a negative correlation between the blockade and functioning, whereas no associations between blockade and negative symptoms or subjective well-being were observed. The results show an association between striatal BPp of dopamine D2/3 receptors in antipsychotic-naïve first-episode patients with schizophrenia and treatment response. Patients with a low BPp have a better treatment response than patients with a high BPp. The results further suggest that functioning may decline at high levels of dopamine receptor blockade.

Motion correction in simultaneous PET/MR brain imaging using sparsely sampled MR navigators: a clinically feasible tool

BackgroundWe present a study performing motion correction (MC) of PET using MR navigators sampled between other protocolled MR sequences during simultaneous PET/MR brain scanning with the purpose of evaluating its clinical feasibility and the potential improvement of image quality.FindingsTwenty-nine human subjects had a 30-min [11C]-PiB PET scan with simultaneous MR including 3D navigators sampled at six time points, which were used to correct the PET image for rigid head motion. Five subjects with motion greater than 4xa0mm were reconstructed into six frames (one for each navigator) which were averaged to one image after MC.The average maximum motion magnitude observed was 3.9u2009±u20092.4xa0mm (1 to 11xa0mm). Visual evaluation by a nuclear medicine physician of the five subjects’ motion corrected rated three of the five images blurred before motion correction, while no images were rated blurred after. The image quality was scored on a scale of 1–5, 5 being best. The score changed from an average of 3.4 before motion correction to 4.0 after. There was no correlation between maximum motion magnitude and rating. Quantitative SUVr scoring did not change markedly with motion correction.ConclusionsSparsely sampled navigators can be used for characterization and correction of head motion. A slight, overall decrease in blurring and an increase in image quality with MC was found, but without impact on clinical interpretation. In future studies with noteworthy motion artifacts, our method is an important and simple-to-use tool to have available for motion correction.