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Serotonin and dopamine are putatively involved in the etiology and treatment of anxiety disorders, but positron emission tomography (PET) studies probing the two neurotransmitters in the same individuals are lacking. The aim of this multitracer PET study was to evaluate the regional expression and co-expression of the transporter proteins for serotonin (SERT) and dopamine (DAT) in patients with social anxiety disorder (SAD). Voxel-wise binding potentials (BPND) for SERT and DAT were determined in 27 patients with SAD and 43 age- and sex-matched healthy controls, using the radioligands [11C]DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile) and [11C]PE2I (N-(3-iodopro-2E-enyl)-2beta-carbomethoxy-3beta-(4′-methylphenyl)nortropane). Results showed that, within transmitter systems, SAD patients exhibited higher SERT binding in the nucleus accumbens while DAT availability in the amygdala, hippocampus, and putamen correlated positively with symptom severity. At a more lenient statistical threshold, SERT and DAT BPND were also higher in other striatal and limbic regions in patients, and correlated with symptom severity, whereas no brain region showed higher binding in healthy controls. Moreover, SERT/DAT co-expression was significantly higher in SAD patients in the amygdala, nucleus accumbens, caudate, putamen, and posterior ventral thalamus, while lower co-expression was noted in the dorsomedial thalamus. Follow-up logistic regression analysis confirmed that SAD diagnosis was significantly predicted by the statistical interaction between SERT and DAT availability, in the amygdala, putamen, and dorsomedial thalamus. Thus, SAD was associated with mainly increased expression and co-expression of the transporters for serotonin and dopamine in fear and reward-related brain regions. Resultant monoamine dysregulation may underlie SAD symptomatology and constitute a target for treatment.

It has been extensively debated whether selective serotonin reuptake inhibitors (SSRIs) are more efficacious than placebo in affective disorders, and it is not fully understood how SSRIs exert their beneficial effects. Along with serotonin transporter blockade, altered dopamine signaling and psychological factors may contribute. In this randomized clinical trial of participants with social anxiety disorder (SAD) we investigated how manipulation of verbally-induced expectancies, vital for placebo response, affect brain monoamine transporters and symptom improvement during SSRI treatment. Twenty-seven participants with SAD (17 men, 10 women), were randomized, to 9 weeks of overt or covert treatment with escitalopram 20 mg. The overt group received correct treatment information whereas the covert group was treated deceptively with escitalopram, described as an active placebo in a cover story. Before and after treatment, patients underwent positron emission tomography (PET) assessments with the [11C]DASB and [11C]PE2I radiotracers, probing brain serotonin (SERT) and dopamine (DAT) transporters. SAD symptoms were measured by the Liebowitz Social Anxiety Scale. Overt was superior to covert SSRI treatment, resulting in almost a fourfold higher rate of responders. PET results showed that SERT occupancy after treatment was unrelated to anxiety reduction and equally high in both groups. In contrast, DAT binding decreased in the right putamen, pallidum, and the left thalamus with overt SSRI treatment, and increased with covert treatment, resulting in significant group differences. DAT binding potential changes in these regions correlated negatively with symptom improvement. Findings support that the anxiolytic effects of SSRIs involve psychological factors contingent on dopaminergic neurotransmission while serotonin transporter blockade alone is insufficient for clinical response.

Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine underpinnings remain largely unknown. A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. Aromatase regulates the synthesis of oestrogens and, of relevance to addiction, is highly expressed in the limbic brain. The present study sought to investigate in vivo aromatase availability in relation to exposure to nicotine in healthy women. Structural magnetic resonance imaging and two [11C]cetrozole positron emission tomography (PET) scans were performed to assess the availability of aromatase before and after administration of nicotine. Gonadal hormones and cotinine levels were measured. Given the region-specific expression of aromatase, a ROI-based approach was employed to assess changes in [11C]cetrozole non-displaceable binding potential. The highest availability of aromatase was found in the right and left thalamus. Upon nicotine exposure, [11C]cetrozole binding in the thalamus was acutely decreased bilaterally (Cohen's d = −0.99). In line, cotinine levels were negatively associated with aromatase availability in the thalamus, although as non-significant trend. These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction. •First in vivo evidence of nicotine effect on aromatase in humans.•Nicotine acutely blocks aromatase in the thalamus of healthy women.•Nicotine absorption levels were tendentially related to aromatase blockade.

Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [ 11 C]DASB and [ 11 C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.

Background 15 O-water positron emission tomography (PET) is considered the gold standard method for non-invasive measurement of cerebral blood flow (CBF). However, previously published average CBF values in healthy subjects have varied greatly and the cause of these variations remains unclear. This study investigates how image reconstruction methods and spatial resolution affect CBF measurements with 15 O-water PET. Methods Eight healthy subjects each underwent dynamic 15 O-water PET scans with continuous arterial blood sampling. Images were reconstructed using two different algorithms; ordered subset expectation maximisation and block sequential regularised expectation maximalisation with varying reconstruction parameters. CBF was estimated for the whole brain, grey matter, and central white matter. Reconstruction-specific effective spatial resolution was estimated using phantom measurements and simulations. Results The mean whole brain CBF was 0.48 mL/cm 3 /min and showed little dependence on the image reconstruction method. Grey matter CBF varied between 0.52 and 0.57 mL/cm 3 /min, and central white matter CBF between 0.20 and 0.28 mL/cm 3 /min. Regional CBF showed great dependence on effective spatial resolution with a negative correlation between grey matter CBF and resolution (r = -0.96) and a positive correlation between central white matter and resolution (r = 0.93). Conclusion This study concludes that grey matter and central white matter CBF, but not whole brain CBF measured with quantitative 15 O-water PET is reconstruction method dependent, mainly due to varying spatial resolution with consequent partial volume effects. Variations in published CBF values cannot be explained solely by reconstruction methods or spatial resolution.

Background Cardiac positron emission tomography (PET) offers non-invasive assessment of perfusion and left ventricular (LV) function from a single dynamic scan. However, no prior assessment of mitral regurgitation severity by PET has been presented. Application of indicator dilution techniques and gated image analyses to PET data enables calculation of forward stroke volume and total LV stroke volume. We aimed to evaluate a combination of these methods for measurement of regurgitant volume (RegVol) and fraction (RegF) using dynamic 15 O-water and 11 C-acetate PET in comparison to cardiovascular magnetic resonance (CMR). Results Twenty-one patients with severe primary mitral valve regurgitation underwent same-day dynamic PET examinations ( 15 O-water and 11 C-acetate) and CMR. PET data were reconstructed into dynamic series with short time frames during the first pass, gated 15 O-water blood pool images, and gated 11 C-acetate myocardial uptake images. PET-based RegVol and RegF correlated strongly with CMR (RegVol: 15 O-water r  = 0.94, 11 C-acetate r  = 0.91 and RegF: 15 O-water r  = 0.88, 11 C-acetate r  = 0.84, p  < 0.001). A systematic underestimation (bias) was found for PET (RegVol: 15 O-water − 11 ± 13 mL, p  = 0.002, 11 C-acetate − 28 ± 16 mL, p  < 0.001 and RegF: 15 O-water − 4 ± 6%, p  = 0.01, 11 C-acetate − 10 ± 7%, p  < 0.001). PET measurements in patients were compared to healthy volunteers ( n  = 18). Mean RegVol and RegF was significantly lower in healthy volunteers compared to patients for both tracers. The accuracy of diagnosing moderately elevated regurgitant volume (> 30mL) was 95% for 15 O-water and 92% for 11 C-acetate. Conclusions LV regurgitation severity quantified using cardiac PET correlated with CMR and showed high accuracy for discriminating patients from healthy volunteers.

Purpose The aim of this study was to explore the cerebral distribution of the tau-specific PET tracer [ 18 F]THK5317 (also known as (S) -[ 18 F]THK5117) retention in different stages of Alzheimer’s disease; and study any associations with markers of hypometabolism and amyloid-beta deposition. Methods Thirty-three individuals were enrolled, including nine patients with Alzheimer’s disease dementia, thirteen with mild cognitive impairment (MCI), two with non-Alzheimer’s disease dementia, and nine healthy controls (five young and four elderly). In a multi-tracer PET design [ 18 F]THK5317, [ 11 C] Pittsburgh compound B ([ 11 C]PIB), and [ 18 F]FDG were used to assess tau pathology, amyloid-beta deposition and cerebral glucose metabolism, respectively. The MCI patients were further divided into MCI [ 11 C]PIB-positive ( n  = 11) and MCI [ 11 C]PIB-negative ( n  = 2) groups. Results Test-retest variability for [ 18 F]THK5317-PET was very low (1.17–3.81 %), as shown by retesting five patients. The patients with prodromal (MCI [ 11 C]PIB-positive) and dementia-stage Alzheimer’s disease had significantly higher [ 18 F]THK5317 retention than healthy controls ( p  = 0.002 and p  = 0.001, respectively) in areas exceeding limbic regions, and their discrimination from this control group (using the area under the curve) was >98 %. Focal negative correlations between [ 18 F]THK5317 retention and [ 18 F]FDG uptake were observed mainly in the frontal cortex, and focal positive correlations were found between [ 18 F]THK5317 and [ 11 C]PIB retentions isocortically. One patient with corticobasal degeneration syndrome and one with progressive supranuclear palsy showed no [ 11 C]PIB but high [ 18 F]THK5317 retentions with a different regional distribution from that in Alzheimer’s disease patients. Conclusions The tau-specific PET tracer [ 18 F]THK5317 images in vivo the expected regional distribution of tau pathology. This distribution contrasts with the different patterns of hypometabolism and amyloid-beta deposition.

O-water positron emission tomography (PET) is considered the gold standard method for non-invasive measurement of cerebral blood flow (CBF). However, previously published average CBF values in healthy subjects have varied greatly and the cause of these variations remains unclear. This study investigates how image reconstruction methods and spatial resolution affect CBF measurements with O-water PET. Eight healthy subjects each underwent dynamic O-water PET scans with continuous arterial blood sampling. Images were reconstructed using two different algorithms; ordered subset expectation maximisation and block sequential regularised expectation maximalisation with varying reconstruction parameters. CBF was estimated for the whole brain, grey matter, and central white matter. Reconstruction-specific effective spatial resolution was estimated using phantom measurements and simulations. The mean whole brain CBF was 0.48 mL/cm /min and showed little dependence on the image reconstruction method. Grey matter CBF varied between 0.52 and 0.57 mL/cm /min, and central white matter CBF between 0.20 and 0.28 mL/cm /min. Regional CBF showed great dependence on effective spatial resolution with a negative correlation between grey matter CBF and resolution (r = -0.96) and a positive correlation between central white matter and resolution (r = 0.93). This study concludes that grey matter and central white matter CBF, but not whole brain CBF measured with quantitative O-water PET is reconstruction method dependent, mainly due to varying spatial resolution with consequent partial volume effects. Variations in published CBF values cannot be explained solely by reconstruction methods or spatial resolution.

The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer’s disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [18F]THK5317 (tau deposition) and [18F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [11C]PIB (amyloid-β deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [18F]THK5317 retention over time, in contrast to significant decreases in [18F]FDG uptake in temporoparietal areas. The pattern of changes in [18F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [18F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [18F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [11C]PIB scan, high [18F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [18F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.

The brain serotonergic system is colocalized and interacts with the neuropeptidergic substance P/neurokinin-1 (SP/NK1) system. Both these neurochemical systems have independently been implicated in stress and anxiety, but interactions between them might be crucial for human anxiety conditions. Here, we examined the serotonin and substance P/neurokinin-1 (SP/NK1) systems individually as well as their overlapping expression in 16 patients with posttraumatic stress disorder (PTSD) and 16 healthy controls. Participants were imaged with the highly selective radiotracers [ 11 C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) and [ 11 C]GR205171 assessing serotonin transporter (SERT) and NK1 receptor availability, respectively. Voxel-wise analyses in the amygdala, our a priori -defined region of interest, revealed increased number of NK1 receptors, but not SERT in the PTSD group. Symptom severity, as indexed by the Clinician-administered PTSD Scale, was negatively related to SERT availability in the amygdala, and NK1 receptor levels moderated this relationship. Exploratory, voxel-wise whole-brain analyses revealed increased SERT availability in the precentral gyrus and posterior cingulate cortex of PTSD patients. Patients, relative to controls, displayed lower degree of overlapping expression between SERT and NK1 receptors in the putamen, thalamus, insula and lateral orbitofrontal gyrus, lower overlap being associated with higher PTSD symptom severity. Expression overlap also explained more of the symptomatology than did either system individually, underscoring the importance of taking interactions between the neurochemical systems into account. Thus, our results suggest that aberrant serotonergic-SP/NK1 couplings contribute to the pathophysiology of PTSD and, consequently, that normalization of these couplings may be therapeutically important.