Serotonin Transporter Imaging in Multiple System Atrophy and Parkinson's Disease.

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized. OBJECTIVES: To use serotonin transporter [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD. METHODS: We performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest. RESULTS: Patients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA-parkinsonian subtype (n = 8) and patients with MSA-cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson's Disease Rating Scale motor score in patients with MSA but not patients with PD. CONCLUSIONS: Brainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Optimization of preprocessing strategies in Positron Emission Tomography (PET) neuroimaging: A [11C]DASB PET study.

Positron Emission Tomography (PET) is an important neuroimaging tool to quantify the distribution of specific molecules in the brain. The quantification is based on a series of individually designed data preprocessing steps (pipeline) and an optimal preprocessing strategy is per definition associated with less noise and improved statistical power, potentially allowing for more valid neurobiological interpretations. In spite of this, it is currently unclear how to design the best preprocessing pipeline and to what extent the choice of each preprocessing step in the pipeline minimizes subject-specific errors. To evaluate the impact of various preprocessing strategies, we systematically examined 384 different pipeline strategies in data from 30 healthy participants scanned twice with the serotonin transporter (5-HTT) radioligand [11C]DASB. Five commonly used preprocessing steps with two to four options were investigated: (1) motion correction (MC) (2) co-registration (3) delineation of volumes of interest (VOI's) (4) partial volume correction (PVC), and (5) kinetic modeling. To quantitatively compare and evaluate the impact of various preprocessing strategies, we used the performance metrics: test-retest bias, within- and between-subject variability, the intraclass-correlation coefficient, and global signal-to-noise ratio. We also performed a power analysis to estimate the required sample size to detect either a 5% or 10% difference in 5-HTT binding as a function of preprocessing pipeline. The results showed a complex downstream dependency between the various preprocessing steps on the performance metrics. The choice of MC had the most profound effect on 5-HTT binding, prior to the effects caused by PVC and kinetic modeling, and the effects differed across VOI's. Notably, we observed a negative bias in 5-HTT binding across test and retest in 98% of pipelines, ranging from 0 to 6% depending on the pipeline. Optimization of the performance metrics revealed a trade-off in within- and between-subject variability at the group-level with opposite effects (i.e. minimization of within-subject variability increased between-subject variability and vice versa). The sample size required to detect a given effect size was also compromised by the preprocessing strategy, resulting in up to 80% increases in sample size needed to detect a 5% difference in 5-HTT binding. This is the first study to systematically investigate and demonstrate the effect of choosing different preprocessing strategies on the outcome of dynamic PET studies. We provide a framework to show how optimal and maximally powered neuroimaging results can be obtained by choosing appropriate preprocessing strategies and we provide recommendations depending on the study design. In addition, the results contribute to a better understanding of methodological uncertainty and variability in preprocessing decisions for future group- and/or longitudinal PET studies.

An open-label positron emission tomography study to evaluate serotonin transporter occupancy following escalating dosing regimens of (R)-(-)-O-desmethylvenlafaxine and racemic O-desmethylvenlafaxine.

SEP-227162 [R(-)-O-desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O-desmethylvenlafaxine (ODV, Pristiq™, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP-227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [11 C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP-227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [11 C]DASB. A baseline, off-medication, scan was performed prior to dosing and a [11 C]DASB PET scan was performed after 72 hr at each dose level. [11 C]DASB binding potential (BPND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BPND (ΔBPND ) from baseline scan to the on-medication scan relative to the baseline BPND value. SEP-227162 and ODV significantly reduced regional distribution volumes and region BPND values in a dose-dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP-227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.

Higher serotonin transporter availability in early-onset obsessive-compulsive disorder patients undergoing escitalopram treatment: A [11 C]DASB PET study.

OBJECTIVE: Early-onset obsessive-compulsive disorder (EOCD) and late-onset obsessive-compulsive disorder (LOCD) are distinct subtypes of obsessive-compulsive disorder (OCD). OCD patients are treated with serotonin reuptake inhibitors, but the difference in serotonin transporter (SERT) availability between medicated EOCD and LOCD is unexplored yet. METHODS: Six EOCD and 6 LOCD patients were enrolled. They underwent serial [11 C]DASB positron emission tomography scans during maintenance therapy with escitalopram, and their plasma concentration of escitalopram was measured simultaneously with the scan. Then, the drug-free binding potential of SERT was calculated by pharmacokinetic-pharmacodynamic modelling. RESULTS: In comparison with LOCD patients, SERT availability was significantly higher in the putamen of EOCD patients (U = 4, p = .026), but not in the caudate nucleus (U = 14, p = .589), thalamus (U = 16, p = .818), and dorsal raphe nucleus (U = 7, p = .093). Binding potential of putamen showed a negative correlation (r = -.580, p = .048) with age of onset of the disease, but not with the Yale-Brown Obsessive Compulsive Scale scores. CONCLUSIONS: These findings indicate that the earlier the age of onset of OCD, the less serotonergic pathology there is and that this difference remains even after long-term serotonin reuptake inhibitor treatment. Clinically, it might suggest that nonserotonergic treatments would be a better option for EOCD patients.

Simple and rapid quantification of serotonin transporter binding using [11C]DASB bolus plus constant infusion.

INTRODUCTION: In-vivo quantification of serotonin transporters (SERT) in human brain has been a mainstay of molecular imaging in the field of neuropsychiatric disorders and helped to explore the underpinnings of several medical conditions, therapeutic and environmental influences. The emergence of PET/MR hybrid systems and the heterogeneity of SERT binding call for the development of efficient methods making the investigation of larger or vulnerable populations with limited scanner time and simultaneous changes in molecular and functional measures possible. We propose [11C]DASB bolus plus constant infusion for these applications and validate it against standard analyses of dynamic PET data. METHODS: [11C]DASB bolus/infusion optimization was performed on data acquired after [11C]DASB bolus in 8 healthy subjects. Subsequently, 16 subjects underwent one scan using [11C]DASB bolus plus constant infusion with Kbol 160-179min and one scan after [11C]DASB bolus for inter-method reliability analysis. Arterial blood sampling and metabolite analysis were performed for all scans. Distribution volumes (VT) were obtained using Logan plots for bolus scans and ratios between tissue and plasma parent activity for bolus plus infusion scans for different time spans of the scan (VT-70 for 60-70min after start of tracer infusion, VT-90 for 75-90min, VT-120 for 100-120min) in 9 subjects. Omitting blood data, binding potentials (BPND) obtained using multilinear reference tissue modeling (MRTM2) and cerebellar gray matter as reference region were compared in 11 subjects. RESULTS: A Kbol of 160min was observed to be optimal for rapid equilibration in thalamus and striatum. VT-70 showed good intraclass correlation coefficients (ICCs) of 0.61-0.70 for thalamus, striatal regions and olfactory cortex with bias ≤5.1% compared to bolus scans. ICCs increased to 0.72-0.78 for VT-90 and 0.77-0.93 for VT-120 in these regions. BPND-90 had negligible bias ≤2.5%, low variability ≤7.9% and ICCs of 0.74-0.87; BPND-120 had ICCs of 0.73-0.90. Low-binding cortical regions and cerebellar gray matter showed a positive bias of ~8% and ICCs 0.57-0.68 at VT-90. Cortical BPND suffered from high variability and bias, best results were obtained for olfactory cortex and anterior cingulate cortex with ICC=0.74-0.75 for BPND-90. High-density regions amygdala and midbrain had a negative bias of -5.5% and -22.5% at VT-90 with ICC 0.70 and 0.63, respectively. CONCLUSIONS: We have optimized the equilibrium method with [11C]DASB bolus plus constant infusion and demonstrated good inter-method reliability with accepted standard methods and for SERT quantification using both VT and BPND in a range of different brain regions. With as little as 10-15min of scanning valid estimates of SERT VT and BPND in thalamus, amygdala, striatal and high-binding cortical regions could be obtained. Blood sampling seems vital for valid quantification of SERT in low-binding cortical regions. These methods allow the investigation of up to three subjects with a single radiosynthesis.

Accelerated HF-rTMS Modifies SERT Availability in the Subgenual Anterior Cingulate Cortex: A Canine [11C]DASB Study on the Serotonergic System.

Repetitive transcranial magnetic stimulation (rTMS) is thought to partly exert its antidepressant action through the serotonergic system. Accelerated rTMS may have the potential to result in similar but faster onset of clinical improvement compared to the classical daily rTMS protocols, but given that delayed clinical responses have been reported, the neurobiological effects of accelerated paradigms remain to be elucidated including on this neurotransmitter system. This sham-controlled study aimed to evaluate the effects of accelerated high frequency rTMS (aHF-rTMS) over the left frontal cortex on the serotonin transporter (SERT) in healthy beagle dogs. A total of twenty-two dogs were randomly divided into three unequal groups: five active stimulation sessions (five sessions in one day, n = 10), 20 active stimulation sessions (five sessions/day for four days, n = 8), and 20 sham stimulation sessions (five sessions/day for four days, n = 4). The SERT binding index (BI) was obtained at baseline, 24 h post stimulation protocol, one month, and three months post stimulation by a [11C]DASB PET scan. It was found that one day of active aHF-rTMS (five sessions) did not result in significant SERT BI changes at any time point. For the 20 sessions of active aHF-rTMS, one month after stimulation the SERT BI attenuated in the sgACC. No significant SERT BI changes were found after 20 sessions of sham aHF-rTMS. A total of four days of active aHF-rTMS modified sgACC SERT BI one month post-stimulation, explaining to some extent the delayed clinical effects of accelerated rTMS paradigms found in human psychopathologies.

Association Between Lack of Insight and Prefrontal Serotonin Transporter Availability in Antipsychotic-Free Patients with Schizophrenia: A High-Resolution PET Study with [11C]DASB.

BACKGROUND: Previous studies suggested a link between serotonergic neurotransmission and impaired insight in schizophrenia. In this study, we examined the relationship between serotonin transporter (SERT) availability in regions of the prefrontal cortex (dorsolateral, ventrolateral, ventromedial, and orbitofrontal cortices) and insight deficits in antipsychotic-free patients with schizophrenia using high-resolution positron emission tomography (PET) with [11C]DASB. METHODS: Nineteen patients underwent [11C]DASB PET and 7-Tesla magnetic resonance imaging scans. To assess SERT availability, the binding potential with respect to non-displaceable compartment (BPND) was derived using the simplified reference tissue model. Patients' level of insight was assessed using the Insight and Treatment Attitude Questionnaire (ITAQ). The relationship between ITAQ scores and [11C]DASB BPND values was examined using the region-of-interest (ROI)- and voxel-based analyses with relevant variables as covariates. The prefrontal cortex and its four subregions were selected as a priori ROIs since the prefrontal cortex has been implicated as the critical neuroanatomical substrate of impaired insight in schizophrenia. RESULTS: The ROI-based analysis revealed that the ITAQ illness insight dimension had significant negative correlations with the [11C]DASB BPND in the left dorsolateral, left orbitofrontal, and bilateral ventrolateral prefrontal cortices. The ITAQ treatment insight dimension had significant negative correlations with the [11C]DASB BPND in the bilateral dorsolateral, left orbitofrontal, and bilateral ventrolateral prefrontal cortices. The ITAQ total score showed significant negative correlations with the [11C]DASB BPND in the bilateral prefrontal cortex and three subregions (dorsolateral, ventrolateral, and orbitofrontal cortices). A supplementary voxel-based analysis corroborated a significant negative association between the ITAQ score and the [11C]DASB BPND in the prefrontal cortices. CONCLUSION: Our study provides in vivo evidence of significant negative correlations between insight deficits and prefrontal SERT availability in patients with schizophrenia, suggesting significant involvement of prefrontal serotonergic signaling in impaired insight, one of the core symptoms of schizophrenia.

Imaging SERT Availability in a Rat Model of L-DOPA-Induced Dyskinesia.

PURPOSE: The development of L-DOPA-induced dyskinesia (LID) is one of the most severe side effects of chronic L-DOPA treatment in Parkinson's disease patients. [11C]DASB positron emission tomography (PET) provides a prominent tool to visualize and quantify serotonin transporter (SERT) pathology in vivo in patients and in animal models. To evaluate the effect of chronic L-DOPA treatment on SERT availability in an animal model of LID, we performed a longitudinal PET study. PROCEDURES: Rats received a unilateral 6-hydroxydopamine (6-OHDA) lesion, and striatal and extrastriatal SERT expression levels were studied with [11C]DASB, a marker of SERT availability, before and after daily treatment with L-DOPA. Dyskinesias were evaluated at different time points over a period of 21 days. RESULTS: [11C]DASB binding was found to be decreased after 6-OHDA lesions in the striatum, cortex, and hippocampus 5 weeks after 6-OHDA injection in the lesioned hemisphere of the rat brain. Chronic L-DOPA priming resulted in a relative preservation of SERT availability in the lesioned and healthy hemisphere compared to baseline measurements. CONCLUSIONS: Our longitudinal PET data support a preservation of SERT availability after the induction of L-DOPA-induced dyskinesia, which is in line with previous reports in dyskinetic PD patients.

Attenuation Correction Approaches for Serotonin Transporter Quantification With PET/MRI.

BACKGROUND: Several MR-based attenuation correction (AC) approaches were developed to conquer the challenging AC in hybrid PET/MR imaging. These AC methods are commonly evaluated on standardized uptake values or tissue concentration. However, in neurotransmitter system studies absolute quantification is more favorable due to its accuracy. Therefore, our aim was to investigate the accuracy of segmentation- and atlas-based MR AC approaches on serotonin transporter (SERT) distribution volumes and occupancy after a drug challenge. METHODS: 18 healthy subjects (7 male) underwent two [11C]DASB PET/MRI measurements in a double-blinded, placebo controlled, cross-over design. After 70 min the selective serotonin reuptake inhibitor (SSRI) citalopram or a placebo was infused. The parameters total and specific volume of distribution (VT, VS = BPP) and occupancy were quantified. All subjects underwent a low-dose CT scan as reference AC method. Besides the standard AC approaches DIXON and UTE, a T1-weighted structural image was recorded to estimate a pseudo-CT based on an MR/CT database (pseudoCT). Another evaluated AC approach superimposed a bone model on AC DIXON. Lastly, an approach optimizing the segmentation of UTE images was analyzed (RESOLUTE). PET emission data were reconstructed with all 6 AC methods. The accuracy of the AC approaches was evaluated on a region of interest-basis for the parameters VT, BPP, and occupancy with respect to the results of AC CT. RESULTS: Variations for VT and BPP were found with all AC methods with bias ranging from -15 to 17%. The smallest relative errors for all regions were found with AC pseudoCT (<|5%|). Although the bias between BPP SSRI and BPP placebo varied markedly with AC DIXON (<|12%|) and AC UTE (<|9%|), a high correlation to AC CT was obtained (r 2∼1). The relative difference of the occupancy for all tested AC methods was small for SERT high binding regions (<|4%|). CONCLUSION: The high correlation might offer a rescaling from the biased parameters VT and BPP to the true values. Overall, the pseudoCT approach yielded smallest errors and the best agreement with AC CT. For SERT occupancy, all AC methods showed little bias in high binding regions, indicating that errors may cancel out in longitudinal assessments.

Serotonin Transporter Binding in the Human Brain After Pharmacological Challenge Measured Using PET and PET/MR.

Introduction: In-vivo quantification of the serotonin transporter (SERT) guided our understanding of many neuropsychiatric disorders. A recently introduced bolus plus constant infusion protocol has been shown to allow the reliable determination of SERT binding with reduced scan time. In this work, the outcomes of two methods, a bolus injection paradigm on a GE PET camera, and a bolus plus infusion paradigm on a combined Siemens PET/MR camera were compared. Methods: A total of seven healthy subjects underwent paired PET and paired PET/MR scans each with intravenous double-blind application of 7.5 mg citalopram or saline in a randomized cross-over study design. While PET scans were performed according to standard protocols and non-displaceable binding potentials (BPND) were calculated using the multi-linear reference tissue model, during PET/MR measurements [11C]DASB was applied as bolus plus constant infusion, and BPND was calculated using the steady state method and data acquired at tracer equilibrium. Occupancies were calculated as the relative decrease in BPND between saline and citalopram scans. Results: During placebo scans, a mean difference in BPND of -0.08 (-11.71%) across all ROIs was found between methods. PET/MR scans resulted in higher BPND estimates than PET scans in all ROIs except the midbrain. A mean difference of -0.19 (-109.40%) across all ROIs between methods was observed for citalopram scans. PET/MR scans resulted in higher BPND estimates than PET scans in all ROIs. For occupancy, a mean difference of 23.12% (21.91%) was observed across all ROIs. PET/MR scans resulted in lower occupancy compared to PET scans in all ROIs except the temporal cortex. While for placebo, BPND of high-binding regions (thalamus and striatum) exhibited moderate reliability (ICC = 0.66), during citalopram scans ICC decreased (0.36-0.46). However, reliability for occupancy remained high (0.57-0.82). Conclusion: Here, we demonstrated the feasibility of reliable and non-invasive SERT quantification using a [11C]DASB bolus plus constant infusion protocol at a hybrid PET/MR scanner, which might facilitate future pharmacological imaging studies. Highest agreement with established methods for quantification of occupancy and SERT BPND at baseline was observed in subcortical high-binding regions.

Brain serotonin transporter binding, plasma arachidonic acid and depression severity: A positron emission tomography study of major depression.

BACKGROUND: Serotonin transporter (5-HTT) binding and polyunsaturated fatty acids (PUFAs) are implicated in major depressive disorder (MDD). Links between the two systems in animal models have not been investigated in humans. METHODS: Using positron emission tomography (PET) and [11C]DASB, we studied relationships between 5-HTT binding potential and plasma levels of PUFAs docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) in medication-free MDD patients (n = 21). PUFAs were quantified using transesterification and gas chromatography. Binding potential BPP, and alternative outcome measures BPF and BPND, were determined for [11C]DASB in six a priori brain regions of interest (ROIs) using likelihood estimation in graphical analysis (LEGA) to calculate radioligand total distribution volume (VT), and a validated hybrid deconvolution approach (HYDECA) that estimates radioligand non-displaceable distribution volume (VND) without a reference region. Linear mixed models used PUFA levels as predictors and binding potential measures as outcomes across the specified ROIs; age and sex as fixed effects; and subject as random effect to account for across-region binding correlations. As nonlinear relationships were observed, a quadratic term was added to final models. RESULTS: AA predicted both 5-HTT BPP and depression severity nonlinearly, described by an inverted U-shaped curve. 5-HTT binding potential mediated the relationship between AA and depression severity. LIMITATIONS: Given the small sample and multiple comparisons, results require replication. CONCLUSIONS: Our findings suggest that AA status may impact depression pathophysiology through effects on serotonin transport. Future studies should examine whether these relationships explain therapeutic effects of PUFAs in the treatment of MDD.

Brain Networks Implicated in Seasonal Affective Disorder: A Neuroimaging PET Study of the Serotonin Transporter.

Background: Seasonal Affective Disorder (SAD) is a subtype of Major Depressive Disorder characterized by seasonally occurring depression that often presents with atypical vegetative symptoms such as hypersomnia and carbohydrate craving. It has recently been shown that unlike healthy people, patients with SAD fail to globally downregulate their cerebral serotonin transporter (5-HTT) in winter, and that this effect seemed to be particularly pronounced in female S-carriers of the 5-HTTLPR genotype. The purpose of this study was to identify a 5-HTT brain network that accounts for the adaption to the environmental stressor of winter in females with the short 5-HTTLPR genotype, a specific subgroup previously reported to be at increased risk for developing SAD. Methods: Nineteen females, either S' carriers (LG- and S-carriers) without SAD (N = 13, mean age 23.6 ± 3.2 year, range 19-28) or S' carriers with SAD (N = 6, mean age 23.7 ± 2.4, range 21-26) were PET-scanned with [11C]DASB during both summer and winter seasons (asymptomatic and symptomatic phase, 38 scans in total) in randomized order, defined as a 12-week interval centered on summer or winter solstice. We used a multivariate Partial Least Squares (PLS) approach with NPAIRS split-half cross-validation, to identify and map a whole-brain pattern of 5-HTT levels that distinguished the brains of females without SAD from females suffering from SAD. Results: We identified a pattern of 5-HTT levels, distinguishing females with SAD from those without SAD; it included the right superior frontal gyrus, brainstem, globus pallidus (bilaterally) and the left hippocampus. Across seasons, female S' carriers without SAD showed nominally higher 5-HTT levels in these regions compared to female S' carriers with SAD, but the group difference was only significant in the winter. Female S' carriers with SAD, in turn, displayed robustly increased 5-HTT levels in the ventral striatum (bilaterally), right orbitofrontal cortex, middle frontal gyrus (bilaterally), extending to the left supramarginal gyrus, left precentral gyrus and left postcentral gyrus during winter compared to female S' carriers without SAD. Limitations: The study is preliminary and limited by small sample size in the SAD group (N = 6). Conclusions: These findings provide novel exploratory evidence for a wintertime state-dependent difference in 5-HTT levels that may leave SAD females with the short 5-HTTLPR genotype more vulnerable to persistent stressors like winter. The affected brain regions comprise a distributed set of areas responsive to emotion, voluntary, and planned movement, executive function, and memory. The preliminary findings provide additional insight into the neurobiological components through which the anatomical distribution of serotonergic discrepancies between individuals genetically predisposed to SAD, but with different phenotypic presentations during the environmental stressor of winter, may constitute a potential biomarker for resilience against developing SAD.

Altered interregional correlations between serotonin transporter availability and cerebral glucose metabolism in schizophrenia: A high-resolution PET study using [11C]DASB and [18F]FDG.

The purpose of the present study was to investigate the patterns of interregional correlations of serotonin transporter (SERT) availability with glucose metabolism using 7-Tesla magnetic resonance imaging (MRI) and high-resolution positron emission tomography (PET) with 11C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([11C]DASB) and [18F]fluorodeoxyglucose ([18F]FDG) in antipsychotic-free patients with schizophrenia in order to shed new light on the disrupted functional connectivity in schizophrenia. Nineteen patients with schizophrenia and 18 healthy controls underwent high-resolution PET and MRI. The binding potential (BPND) of [11C]DASB and standardized uptake value ratio (SUVR) of [18F]FDG were obtained. In SERT availability, the region of interest (ROI)-based analyses showed no significant group differences in any region, except for the anterior hippocampus where the SERT availability was lower in patients with schizophrenia than in controls. The ROI- and voxel-based analyses revealed that the [18F]FDG SUVR values were significantly lower in patients than in controls in the right superior frontal gyrus and medial part of the left superior frontal gyrus. Regarding the interregional correlations of [11C]DASB BPND with [18F]FDG SUVR, more widespread positive correlations across the brain regions were observed in control subjects than in patients with schizophrenia. Notably, the patients and control subjects showed statistically significant differences in correlations between the SERT availability in the parietal and temporal cortices and the glucose metabolism in the posterior cingulate cortex. These results suggest abnormal functional connectivity between the higher-order cortical regions in schizophrenia and a possible important role of the posterior cingulate gyrus and its related circuitry in the pathophysiology of schizophrenia.

In Vivo Evaluation of 11C-DASB for Quantitative SERT Imaging in Rats and Mice.

UNLABELLED: Serotonin, or 5-hydroxytryptamine (5-HT), plays a key role in the central nervous system and is involved in many essential neurologic processes such as mood, social behavior, and sleep. The serotonin transporter ligand (11)C-3-amino-4(2-dimethylaminomethyl-phenylsufanyl)-benzonitrile ((11)C-DASB) has been used to determine nondisplaceable binding potential (BPND), which is defined as the quotient of the available receptor density (Bavail) and the apparent equilibrium dissociation rate constant (1/appKD) under in vivo conditions. Because of the increasing number of animal models of human diseases, there is a pressing need to evaluate the applicability of (11)C-DASB to rats and mice. Here, we assessed the feasibility of using (11)C-DASB for quantification of serotonin transporter (SERT) density and affinity in vivo in rats and mice. METHODS: Rats and mice underwent 4 PET scans with increasing doses of the unlabeled ligand to calculate Bavail and appKD using the multiple-ligand concentration transporter assay. An additional PET scan was performed to calculate test-retest reproducibility and reliability. BPND was calculated using the simplified reference tissue model, and the results for different reference regions were compared. RESULTS: Displaceable binding of (11)C-DASB was found in all brain regions of both rats and mice, with the highest binding being in the thalamus and the lowest in the cerebellum. In rats, displaceable binding was largely reduced in the cerebellar cortex, which in mice was spatially indistinguishable from cerebellar white matter. Use of the cerebellum with fully saturated binding sites as the reference region did not lead to reliable results. Test-retest reproducibility in the thalamus was more than 90% in both mice and rats. In rats, Bavail, appKD, and ED50 were 3.9 ± 0.4 pmol/mL, 2.2 ± 0.4 nM, and 12.0 ± 2.6 nmol/kg, respectively, whereas analysis of the mouse measurements resulted in inaccurate fits due to the high injected tracer mass. CONCLUSION: Our data showed that in rats, (11)C-DASB can be used to quantify SERT density with good reproducibility. BPND agreed with the distribution of SERT in the rat brain. It remains difficult to estimate quantitative parameters accurately from mouse measurements because of the high injected tracer mass and underestimation of the binding parameters due to high displaceable binding in the reference region.

Time-course of serotonin transporter occupancy by single dose of three SSRIs in human brain: A positron emission tomography study with [(11)C]DASB.

Sixteen healthy volunteers were enrolled and divided into four groups according to the single administration of 10mg or 20mg escitalopram, 50mg sertraline, or 20mg paroxetine. Four positron emission tomography scans with [(11)C]DASB were performed on each subject, the first prior to taking the drug, followed by the others at 4, 24, and 48h after. Serotonin transporter occupancies of the drugs at each time point were calculated. All drugs showed maximum occupancy at 4h after dosing and then decreasing occupancies with time. Escitalopram and sertraline showed high occupancies of 69.1-77.9% at 4h, remaining at 52.8-57.8% after 48h. On the other hand, paroxetine showed relatively low occupancy of 44.6%, then decreasing to 10.3% at 48h. Escitalopram (both 10mg and 20mg) and sertraline (50mg) showed high and sustained occupancy. Paroxetine (20mg) showed relatively low and rapidly decreasing occupancy, possibly due to the low plasma concentration by single dosing schedule. Applying the reported concentration of multiple dosing, 20mg paroxetine will induce over 80% occupancy. The present study suggested that these drugs and doses would be sufficient for the treatment of depression.

Self-transcendence trait and its relationship with in vivo serotonin transporter availability in brainstem raphe nuclei: An ultra-high resolution PET-MRI study.

Self-transcendence is an inherent human personality trait relating to the experience of spiritual aspects of the self. We examined the relationship between self-transcendence and serotonin transporter (SERT) availability in brainstem raphe nuclei, which are collections of five different serotonergic nuclei with rostro-caudal extension, using ultra-high resolution magnetic resonance imaging (MRI) and positron emission tomography (PET) with (11)C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([(11)C]DASB) to elucidate potential roles of serotonergic neuronal activities in this personality trait. Sixteen healthy subjects completed 7.0T MRI and High Resolution Research Tomograph (HRRT) PET. The regions of interest (ROIs) included the dorsal raphe nucleus (R1), median raphe nucleus (R2), raphe pontis (R3), and the caudal raphe nuclei (R4 and R5). For the estimation of SERT availability, the binding potential (BPND) was derived using the simplified reference tissue model (SRTM2). The Temperament and Character Inventory was used to measure self-transcendence. The analysis revealed that the self-transcendence total score had a significant negative correlation with the [(11)C]DASB BPND in the caudal raphe (R5). The subscale score for spiritual acceptance was significantly negatively correlated with the [(11)C]DASB BPND in the median raphe nucleus (R2). The results indicate that the self-transcendence trait is associated with SERT availability in specific raphe subnuclei, suggesting that the serotonin system may serve as an important biological basis for human self-transcendence. Based on the connections of these nuclei with cortico-limbic and visceral autonomic structures, the functional activity of these nuclei and their related neural circuitry may play a crucial role in the manifestation of self-transcendence.

Serotonin transporter availability in thalamic subregions in schizophrenia: a study using 7.0-T MRI with [(11)C]DASB high-resolution PET.

The serotonin transporter (SERT) is an integral protein that provides an index of serotonergic innervation. Until recently, few studies have investigated SERT binding in thalamic subregions in schizophrenia. The purpose of this study was to examine SERT availability in thalamic subdivisions (anterior nucleus, mediodorsal nucleus, and pulvinar) using 7.0-T magnetic resonance imaging (MRI) and high-resolution positron emission tomography (PET) with (11)C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([(11)C]DASB) in schizophrenia. Antipsychotic-free patients with schizophrenia (n=12) and healthy controls (n=15) underwent PET and MRI scans. For SERT availability, the binding potential with respect to non-displaceable compartment (BPND) was derived using the simplified reference tissue model (SRTM2). The analysis revealed that there were no significant differences in SERT availability between the two groups. In patients with schizophrenia, the severity of negative symptoms had a negative correlation with SERT availability in the anterior nucleus of the left thalamus. The present study did not reveal significant differences in SERT availability in thalamic subdivisions between patients with schizophrenia and control subjects. The association of SERT availability in the anterior nucleus with negative symptoms may suggest a role for the anterior thalamic nucleus in the pathophysiology of symptoms of schizophrenia. The ultra-high resolution imaging system could be an important asset for in vivo psychiatric research by combining structural and molecular information.

Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation: A Positron Emission Tomography Study.

BACKGROUND: An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention. METHODS: A double-blind, randomized, placebo-controlled study included 63 healthy female volunteers (mean age 24.3 ± 4.9 years) with regular menstrual cycles between 23 and 35 days. Participants were randomized to active (goserelin [GnRHa] 3.6 mg implant) or placebo intervention. Sixty women completed follow-up and entered the analyses. Primary outcome measures were changes from baseline in depressive symptoms assessed on the 17-item Hamilton Depression Rating Scale and SERT binding as imaged by [(11)C]DASB positron emission tomography. Outcome measures were acquired at baseline in the follicular phase (cycle day 6.6 ± 2.2) and at follow-up (16.2 ± 2.6 days after intervention start). RESULTS: Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p = .003) and relative to placebo (p = .02), which were positively associated with net decreases in estradiol levels (p = .02) from baseline within the GnRHa group. Depressive symptoms were associated with increases in neocortical SERT binding in the GnRHa group relative to placebo (p = .003). CONCLUSIONS: Our data imply both serotonergic signaling and estradiol in the mechanisms by which sex-steroid hormone fluctuations provoke depressive symptoms and thus provide a rationale for future preventive strategies in high-risk groups.

Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder.

BACKGROUND: Several lines of evidence implicate abnormal serotonergic function in suicidal behavior and completed suicide, including low serotonin transporter binding in postmortem studies of completed suicide. We have also reported low in vivo serotonin transporter binding in major depressive disorder (MDD) during a major depressive episode using positron emission tomography (PET) with [(11)C]McN5652. We quantified regional brain serotonin transporter binding in vivo in depressed suicide attempters, depressed nonattempters, and healthy controls using PET and a superior radiotracer, [(11)C]DASB. METHODS: Fifty-one subjects with DSM-IV current MDD, 15 of whom were past suicide attempters, and 32 healthy control subjects underwent PET scanning with [(11)C]DASB to quantify in vivo regional brain serotonin transporter binding. Metabolite-corrected arterial input functions and plasma free-fraction were acquired to improve quantification. RESULTS: Depressed suicide attempters had lower serotonin transporter binding in midbrain compared with depressed nonattempters (p = .031) and control subjects (p = .0093). There was no difference in serotonin transporter binding comparing all depressed subjects with healthy control subjects considering six a priori regions of interest simultaneously (p = .41). CONCLUSIONS: Low midbrain serotonin transporter binding appears to be related to the pathophysiology of suicidal behavior rather than of major depressive disorder. This is consistent with postmortem work showing low midbrain serotonin transporter binding capacity in depressed suicides and may partially explain discrepant in vivo findings quantifying serotonin transporter in depression. Future studies should investigate midbrain serotonin transporter binding as a predictor of suicidal behavior in MDD and determine the cause of low binding.