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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.

Aromatase, the enzyme that in the brain converts testosterone and androstenedione to estradiol and estrone, respectively, is a putative key factor in psychoneuroendocrinology. In vivo assessment of aromatase was performed to evaluate tracer kinetic models and optimal scan duration, for quantitative analysis of the aromatase positron emission tomography (PET) ligand [11 C]cetrozole. Anatomical magnetic resonance and 90-min dynamic [11 C]cetrozole PET-CT scans were performed on healthy women. Volume of interest (VOI)-based analyses with a plasma-input function were performed using the single-tissue and two-tissue (2TCM) reversible compartment models and plasma-input Logan analysis. Additionally, the simplified reference tissue model (SRTM), Logan reference tissue model (LRTM), and standardized uptake volume ratio model, with cerebellum as reference region, were evaluated. Parametric images were generated and regionally averaged voxel values were compared with VOI-based analyses of the reference tissue models. The optimal reference model was used for evaluation of a decreased scan duration. Differences between the plasma-input- and reference tissue-based methods and comparisons between scan durations were assessed by linear regression. The [11 C]cetrozole time-activity curves were best described by the 2TCM. SRTM nondisplaceable binding potential (BPND ), with cerebellum as reference region, can be used to estimate [11 C]cetrozole binding and generated robust and quantitatively accurate results for a reduced scan duration of 60 min. Receptor parametric mapping, a basis function implementation of SRTM, as well as LRTM, produced quantitatively accurate parametric images, showing BPND at the voxel level. As PET tracer, [11 C]cetrozole can be employed for relatively short brain scans to measure aromatase binding using a reference tissue-based approach.

[F-18]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [F-18]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R-1) parametric images. Nine AD patients and nine controls underwent 90 min [F-18]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R-1 images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 +/- 4 min for AD patients and in putamen at 20 +/- 0 min in controls. Over all regions and subjects, SUVR20-40-1 correlated best with DVR-1, R-2 = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R-2 = 0.93 for SUVR20-40-1; R-2 = 0.94 for R-1). SUVR20-40 allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R-1 with 40 min scan duration.

Animal studies indicate that substance P (SP) and its preferred neurokinin-1 (NK1) receptor modulate stress and anxiety-related behavior. Alterations in the SP-NK1 system have also been observed in human anxiety disorders, yet little is known about the relation between this system and individual differences in personality traits associated with anxiety propensity and approach-avoidance behavior, including trait anxiety, neuroticism, and extraversion. Exploring this relation could provide important insights into the neurobiological underpinnings of human anxiety and the etiology of anxiety disorders, as anxious traits are associated with increased susceptibility to develop psychopathological conditions. Here we examined the relationship between central NK1 receptor availability and self-rated measures of trait anxiety, neuroticism, and extraversion. The amygdala was chosen as the primary region of interest since this structure has been suggested to mediate the effect of the SP-NK1 system on anxiety. Anxious traits and NK1 receptor availability, determined with positron emission tomography and the radiotracer [11C]GR205171, were measured in 17 healthy individuals. Voxel-wise analyses showed a significant positive correlation between bilateral amygdala NK1 receptor availability and trait anxiety, and a trend in similar direction was observed for neuroticism. Conversely, extraversion was found to be negatively associated with amygdala NK1 receptor availability. Extraversion also correlated negatively with the NK1 measure in the cuneus/precuneus and fusiform gyrus according to exploratory whole-brain analyses. In conclusion, our findings indicate that amygdala NK1 receptor availability is associated with anxiety-related personality traits in healthy subjects, consistent with a modulatory role for the SP-NK1 system in human anxiety.

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 [(18)F]THK5317 (tau deposition) and [(18)F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [(11)C]PIB (amyloid-β deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [(18)F]THK5317 retention over time, in contrast to significant decreases in [(18)F]FDG uptake in temporoparietal areas. The pattern of changes in [(18)F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [(18)F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [(18)F]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 [(11)C]PIB scan, high [(18)F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [(18)F]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.Molecular Psychiatry advance online publication, 16 May 2017; doi:10.1038/mp.2017.108.

Animal studies indicate that substance P (SP) and its preferred neurokinin-1 (NK1) receptor modulate stress and anxiety-related behavior. Alterations in the SP-NK1 system have also been observed in human anxiety disorders, yet little is known about the relation between this system and individual differences in personality traits associated with anxiety propensity and approach-avoidance behavior, including trait anxiety, neuroticism, and extraversion. Exploring this relation could provide important insights into the neurobiological underpinnings of human anxiety and the etiology of anxiety disorders, as anxious traits are associated with increased susceptibility to develop psychopathological conditions. Here we examined the relationship between central NK1 receptor availability and self-rated measures of trait anxiety, neuroticism, and extraversion. The amygdala was chosen as the primary region of interest since this structure has been suggested to mediate the effect of the SP-NK1 system on anxiety. Anxious traits and NK1 receptor availability, determined with positron emission tomography and the radiotracer [11C]GR205171, were measured in 17 healthy individuals. Voxel-wise analyses showed a significant positive correlation between bilateral amygdala NK1 receptor availability and trait anxiety, and a trend in similar direction was observed for neuroticism. Conversely, extraversion was found to be negatively associated with amygdala NK1 receptor availability. Extraversion also correlated negatively with the NK1 measure in the cuneus/precuneus and fusiform gyrus according to exploratory whole-brain analyses. In conclusion, our findings indicate that amygdala NK1 receptor availability is associated with anxiety-related personality traits in healthy subjects, consistent with a modulatory role for the SP-NK1 system in human anxiety.

Supplement: 1, Meeting Abstract: BPS01-3

Because a correlation between tau pathology and the clinical symptoms of Alzheimer's disease (AD) has been hypothesized, there is increasing interest in developing PET tracers that bind specifically to tau protein. The aim of this study was to evaluate tracer kinetic models for quantitative analysis and generation of parametric images for the novel tau ligand (S)-(18)F-THK5117. METHODS: 9 subjects (5 with AD, 4 with mild cognitive impairment) received a 90 min dynamic (S)-(18)F-THK5117 PET scan. Arterial blood was sampled for measurement of blood radioactivity and metabolite analysis. VOI-based analysis was performed using plasma-input models; single-tissue and two-tissue (2TCM) compartment models and plasma-input Logan, and reference tissue models; simplified reference tissue model (SRTM), reference Logan and standardised uptake value ratio (SUVr). Cerebellum grey matter was used as reference region. Voxel-level analysis was performed using basis function implementations of SRTM, reference Logan and SUVr. Regionally averaged voxel values were compared to VOI-based values from the optimal reference tissue model and simulations were made to assess accuracy and precision. In addition to 90 min, initial 40 and 60 min data were analysed. RESULTS: Plasma-input Logan distribution volume ratio (DVR)-1 values agreed well with 2TCM DVR-1 values (R2=0.99, slope=0.96). SRTM binding potential (BPND) and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 (R2=1.00, slope≈1.00) while SUVr70-90-1 values correlated less well and overestimated binding. Agreement between parametric methods and SRTM was best for reference Logan (R2=0.99, slope=1.03). SUVr70-90-1 values were almost 3 times higher than BPND values in white matter and 1.5 times higher in grey matter. Simulations showed poorer accuracy and precision for SUVr70-90-1 values than for the other reference methods. SRTM BPND and reference Logan DVR-1 values were not affected by a shorter scan durat

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.

In idiopathic Parkinson disease and atypical parkinsonian disorders, central dopaminergic and overall brain functional activity are altered to different degrees, causing difficulties in achieving an unambiguous clinical diagnosis. A dual examination using I-123-FP-CIT (I-123-N-omega-fluoropropyl- 2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane, or I-123-ioflupane) SPECT and F-18-FDG PET provides complementary information on dopamine transporter (DAT) availability and overall brain functional activity, respectively. Parametric images based on a single, dynamic C-11-PE2I (N-(3-iodoprop-2E-enyl)-2 beta-carbomethoxy-3 beta-(4-methyl-phenyl) nortropane) scan potentially supply both DAT availability (nondisplaceable binding potential [BPND]) and relative cerebral blood flow (relative delivery [R-1]) at voxel level. This study aimed to evaluate the validity of C-11-PE2I PET against the dual-modality approach using I-123-FP-CIT SPECT and F-18-FDG PET. Methods: Sixteen patients with parkinsonian disorders had a dual examination with F-18-FDG PET and I-123-FP-CIT SPECT following clinical routines and additionally an experimental C-11-PE2I PET scan. Parametric BPND and R-1 images were generated using receptor parametric mapping with the cerebellum as a reference. T1-weighted MR imaging was used for automated definition of volumes of interest (VOI). The DAT VOIs included the basal ganglia, whereas the overall brain functional activity was examined using VOIs across the brain. BPND and R-1 values were compared with normalized I-123-FP-CIT and F-18-FDG uptake values, respectively, using Pearson correlations and regression analyses. In addition, 2 masked interpreters evaluated the images visually, in both the routine and the experimental datasets, for comparison of patient diagnoses. Results: Parametric C-11-PE2I BPND and R-1 images showed high consistency with I-123-FP-CIT SPECT and F-18-FDG PET images. Correlations between C-11-PE2I BPND and I-123-FP-CIT uptake ratios were

The neurokinin-1 (NK1) receptor is abundantly expressed in the fear circuitry of the brain, including the amygdala, where it modulates stress and anxiety. Despite its proposed involvement in psychopathology, only a few studies of NK1 receptor availability in human subjects with anxiety disorders exist. Here, we compared NK1 receptor availability in patients with social anxiety disorder (SAD; n = 17) and healthy controls (n = 17) using positron emission tomography and the radiotracer [(11)C]GR205171. The Patlak Graphical plot using a cerebellar reference region was used to model the influx parameter, Ki measuring NK1 receptor availability. Voxel-wise statistical parametric mapping analyses revealed increased NK1 receptor availability specifically in the right amygdala in SAD patients relative to controls. Thus, we demonstrate that exaggerated social anxiety is related to enhanced NK1 receptor availability in the amygdala. This finding supports the contribution of NK1 receptors not only in animal models of stress and anxiety but also in humans with anxiety disorders., De två sista författarna delar sistaförfattarskapet.

Meeting Abstract: 413

High interstitial fluid pressure (IFP) in colorectal cancer metastases may decrease the uptake and, thus, the effects of antitumor drugs. Imatinib, a selective inhibitor of platelet-derived growth factor receptors, and anakinra, an interleukin-1 receptor antagonist, respectively, increase drug uptake or decrease IFP in preclinical models of carcinoma. Drug-induced decrease in IFP in human metastases has not been objectively shown but should be reflected by an increase in water-perfusable tissue fraction (PTF) or tumor blood flow (TBF) using O-15-water PET/CT and kinetic modeling. Hence, the aim of this study was to assess the effects of imatinib and anakinra on PTF and TBF in colorectal cancer metastases in patients. Methods: Nine patients with documented progressive disease despite all established therapy underwent O-15-water PET/CT at baseline and at 2 d and 6-7 d after the start of oral administration of imatinib (400 mg/d). After a washout period of 1 wk, the protocol was repeated with anakinra (100 mg/d) subcutaneously. Six patients underwent a second baseline scan on the same day to assess reproducibility of PTF and TBF measurements. Volumes of interest were drawn over liver metastases and aorta. PTF and TBF were calculated using the standard single-tissue-compartment model. Results: Imatinib administration during 6-7 d increased PTF from 0.62 +/- 0.12 to 0.69 +/- 0.13, compared with baseline and day 2 (P = 0.02, Wilcoxon test). No significant changes were found in TBF. PTF values were no longer significantly different from baseline 1 wk after the last imatinib dosage. Anakinra induced no significant change in PTF or TBF. The repeatability coefficients of PTF and TBF in liver lesions were 22% and 28%, respectively. Conclusion: Imatinib increases PTF of colorectal cancer metastases in patients and hence may increase the delivery of antitumor drugs. O-15-water PET/CT and kinetic modeling provide insights into the microenvironment of human cancers.