The effects of catecholamine depletion on the neural response to fearful faces in remitted depression

Recent evidence suggests that increased psychophysiological response to negatively valenced emotional stimuli found in major depressive disorder (MDD) may be associated with reduced catecholaminergic neurotransmission. Fourteen unmedicated, remitted subjects with MDD (RMDD) and 13 healthy control subjects underwent catecholamine depletion with oral α-methyl-para-tyrosine (AMPT) in a randomized, placebo-controlled, double-blind crossover trial. Subjects were exposed to fearful (FF) and neutral faces (NF) during a scan with [15O]H2O positron emission tomography to assess the brain-catecholamine interaction in brain regions previously associated with emotional face processing. Treatment with AMPT resulted in significantly increased, normalized cerebral blood flow (CBF) in the left inferior temporal gyrus (ITG) and significantly decreased CBF in the right cerebellum across conditions and groups. In RMDD, flow in the left posterior cingulate cortex (PCC) increased significantly in the FF compared to the NF condition after AMPT, but remained unchanged after placebo, whereas healthy controls showed a significant increase under placebo and a significant decrease under AMPT in this brain region. In the left dorsolateral prefrontal cortex (DLPFC), flow decreased significantly in the FF compared to the NF condition under AMPT, and increased significantly under placebo in RMDD, whereas healthy controls showed no significant differences. Differences between AMPT and placebo of within-session changes in worry-symptoms were positively correlated with the corresponding changes in CBF in the right subgenual prefrontal cortex in RMDD. In conclusion, this study provided evidence for a catecholamine-related modulation of the neural responses to FF expressions in the left PCC and the left DLPFC in subjects with RMDD that might constitute a persistent, trait-like abnormality in MDD.

Dispersal Modeling of Fish Early Life Stages: Sensitivity with Application to Atlantic Cod in the Western Gulf of Maine

As an initial step in establishing mechanistic relationships between environmental variability and recruitment in Atlantic cod Gadhus morhua along the coast of the western Gulf of Maine, we assessed transport success of larvae from major spawning grounds to nursery areas with particle tracking using the unstructured grid model FVCOM (finite volume coastal ocean model). In coastal areas, dispersal of early planktonic life stages of fish and invertebrate species is highly dependent on the regional dynamics and its variability, which has to be captured by our models. With state-of-the-art forcing for the year 1995, we evaluate the sensitivity of particle dispersal to the timing and location of spawning, the spatial and temporal resolution of the model, and the vertical mixing scheme. A 3 d frequency for the release of particles is necessary to capture the effect of the circulation variability into an averaged dispersal pattern of the spawning season. The analysis of sensitivity to model setup showed that a higher resolution mesh, tidal forcing, and current variability do not change the general pattern of connectivity, but do tend to increase within-site retention. Our results indicate strong downstream connectivity among spawning grounds and higher chances for successful transport from spawning areas closer to the coast. The model run for January egg release indicates 1 to 19 % within-spawning ground retention of initial particles, which may be sufficient to sustain local populations. A systematic sensitivity analysis still needs to be conducted to determine the minimum mesh and forcing resolution that adequately resolves the complex dynamics of the western Gulf of Maine. Other sources of variability, i.e. large-scale upstream forcing and the biological environment, also need to be considered in future studies of the interannual variability in transport and survival of the early life stages of cod.

Metabotropic glutamate receptor 5 binding in patients with obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a disabling, mostly chronic, psychiatric condition with significant social and economic impairments and is a major public health issue. However, numerous patients are resistant to currently available pharmacological and psychological interventions. Given that recent animal studies and magnetic resonance spectroscopy research points to glutamate dysfunction in OCD, we investigated the metabotropic glutamate receptor 5 (mGluR5) in patients with OCD and healthy controls. We determined mGluR5 distribution volume ratio (DVR) in the brain of ten patients with OCD and ten healthy controls by using [11C]ABP688 positron-emission tomography. As a clinical measure of OCD severity, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was employed. We found no significant global difference in mGluR5 DVR between patients with OCD and healthy controls. We did, however, observe significant positive correlations between the Y-BOCS obsession sub-score and mGluR5 DVR in the cortico-striatal-thalamo-cortical brain circuit, including regions of the amygdala, anterior cingulate cortex, and medial orbitofrontal cortex (Spearman's ρ's⩾ = 0.68, p < 0.05). These results suggest that obsessions in particular might have an underlying glutamatergic pathology related to mGluR5. The research indicates that the development of metabotropic glutamate agents would be useful as a new treatment for OCD.

Comparative Behavioral and Neural Effects of Tryptophan and Catecholamine Depletion in Remitted Depression

Background: Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catechominergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber’s selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Methods: Using identical neuroimaging procedures with [18F] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared to healthy controls in a double-blind, randomized, crossover design. Results: While TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex (PCC). While we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. Conclusions: In conclusion, this study showed that serotonin and catecholamines play common and differential roles in the pathophysiology of depression.

Time-course of "off-line" prefrontal rTMS effects--a PET study.

Low-frequency "off-line" repetitive transcranial magnetic stimulation (rTMS) over the course of several minutes has attained considerable attention as a research tool in cognitive neuroscience due to its ability to induce functional disruptions of brain areas. This disruptive rTMS effect is highly valuable for revealing a causal relationship between brain and behavior. However, its influence on remote interconnected areas and, more importantly, the duration of the induced neurophysiological effects, remain unknown. These aspects are critical for a study design in the context of cognitive neuroscience. In order to investigate these issues, 12 healthy male subjects underwent 8 H(2)(15)O positron emission tomography (PET) scans after application of long-train low-frequency rTMS to the right dorsolateral prefrontal cortex (DLPFC). Immediately after the stimulation train, regional cerebral blood flow (rCBF) increases were present under the stimulation site as well as in other prefrontal cortical areas, including the ventrolateral prefrontal cortex (VLPFC) ipsilateral to the stimulation site. The mean increases in rCBF returned to baseline within 9 min. The duration of this unilateral prefrontal rTMS effect on rCBF is of particular interest to those who aim to influence behavior in cognitive paradigms that use an "off-line" approach.

Echinococcus metacestode: in search of viability markers

Epidemiological studies have demonstrated that most humans infected with Echinococcus spp. exhibit resistance to disease. When infection leads to disease, the parasite is partially controlled by host immunity: in case of immunocompetence, the normal alveolar echinococcosis (AE) or cystic echinococcosis (CE) situation, the metacestode grows slowly, and first clinical signs appear years after infection; in case of impaired immunity (AIDS; other immunodeficiencies), uncontrolled proliferation of the metacestode leads to rapidly progressing disease. Assessing Echinococcus multilocularis viability in vivo following therapeutic interventions in AE patients may be of tremendous benefit when compared with the invasive procedures used to perform biopsies. Current options are F18-fluorodeoxyglucose-positron emission tomography (FDG-PET), which visualizes periparasitic inflammation due to the metabolic activity of the metacestode, and measurement of antibodies against recEm18, a viability-associated protein, that rapidly regresses upon metacestode inactivation. For Echinococcus granulosus, similar prognosis-associated follow-up parameters are still lacking but a few candidates may be listed. Other possible markers include functional and diffusion-weighted Magnetic Resonance Imaging (MRI), and measurement of products from the parasite (circulating antigens or DNA), and from the host (inflammation markers, cytokines, or chemokines). Even though some of them have been promising in pilot studies, none has been properly validated in an appropriate number of patients until now to be recommended for further use in clinical settings. There is therefore still a need to develop reliable tools for improved viability assessment to provide the sufficient information needed to reliably withdraw anti-parasite benzimidazole chemotherapy, and a basis for the development of new alternative therapeutic tools.

Development of a specific tracer for metabolic imaging of alveolar echinococcosis: A preclinical study

Positron emission tomography (PET)-computed tomography (CT) using [18F]-fluorodeoxyglucose (FDG) (FDG-PET/CT) is a valuable method for initial staging and follow up of patients with alveolar echinococcosis (AE). However, the cells responsible for FDG uptake have not been clearly identified. The main goal of our study was to evaluate the uptake of PET tracers by the cells involved in the host-parasite reaction around AE lesions as the first step to develop a specific PET tracer that would allow direct assessment of parasite viability in AE. Candidate molecules ([18F]-fluorotyrosine (FET), [18F]-fluorothymidine (FLT), and [18F]-fluorometylcholine (FMC), were compared to FDG by in vitro studies on human leukocytes and parasite vesicles. Our results confirmed that FDG was mainly consumed by immune cells and showed that FLT was the best candidate tracer for parasite metabolism. Indeed, parasite cells exhibited high uptake of FLT. We also performed PET/CT scans in mice infected intraperitoneally with E. multilocularis metacestodes. PET images showed no FDG or FLT uptake in parasitic lesions. This preliminary study assessed the metabolic activity of human leukocytes and AE cells using radiolabeling. Future studies could develop a specific PET tracer for AE lesions to improve lesion detection and echinococcosis treatment in patients. Our results demonstrated that a new animal model is needed for preclinical PET imaging to better mimic human hepatic and/or periparasitic metabolism.

Association of long-term nicotine abstinence with normal metabotropic glutamate receptor-5 binding

BACKGROUND Nicotine addiction is a major public health problem and is associated with primary glutamatergic dysfunction. We recently showed marked global reductions in metabotropic glutamate receptor type 5 (mGluR5) binding in smokers and recent ex-smokers (average abstinence duration of 25 weeks). The goal of this study was to examine the role of mGluR5 downregulation in nicotine addiction by investigating a group of long-term ex-smokers (abstinence >1.5 years), and to explore associations between mGluR5 binding and relapse in recent ex-smokers. METHODS Images of mGluR5 receptor binding were acquired in 14 long-term ex-smokers, using positron emission tomography with radiolabeled [11C]ABP688, which binds to an allosteric site with high specificity. RESULTS Long-term ex-smokers and individuals who had never smoked showed no differences in mGluR5 binding in any of the brain regions examined. Long-term ex-smokers showed significantly higher mGluR5 binding than recent ex-smokers, most prominently in the frontal cortex (42%) and thalamus (57%). CONCLUSIONS Our findings suggest that downregulation of mGluR5 is a pathogenetic mechanism underlying nicotine dependence and the high relapse rate in individuals previously exposed to nicotine. Therefore, mGluR5 receptor binding appears to be an effective biomarker in smoking and a promising target for the discovery of novel medication for nicotine dependence and other substance-related disorders.

Serotonin versus catecholamine deficiency: behavioral and neural effects of experimental depletion in remitted depression

Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catecholaminergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber's selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Using identical neuroimaging procedures with [(18)F] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared with healthy controls in a double-blind, randomized, crossover design. Although TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex. Although we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. In conclusion, this study showed that serotonin and catecholamines have common and differential roles in the pathophysiology of depression.

Copper-64 Labeled Macrobicyclic Sarcophagine Coupled to a GRP Receptor Antagonist Shows Great Promise for PET Imaging of Prostate Cancer

The gastrin-releasing peptide receptor (GRPr) is an important molecular target for the visualization and therapy of tumors and can be targeted with radiolabeled bombesin derivatives. The present study aims to develop statine-based bombesin receptor antagonists suitable for labeling with 64Cu for imaging by positron emission tomography (PET). The potent GRPr antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 was conjugated to the sarcophagine (3,6,10,13,16,19-hexaazabicyclo[6.6.6] icosane=Sar) derivative 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar) via PEG4 (LE1) and PEG2 (LE2) spacers and radiolabeled with 64Cu2+ with >95% yield and specific activities of about 100 MBq/nmol. Both Cu(II) conjugates have high affinity for GRPr (IC50: natCu-LE1, 1.4±0.1 nM; natCu-LE2, 3.8±0.6 nM). The antagonistic properties of both conjugates were confirmed by Ca2+-flux measurements. Biodistribution studies of Cu-64-LE1 exhibited specific targeting of the tumor (19.6±4.7% IA/g at 1 h p.i.) and GRPr-positive organs. Biodistribution and PET images at 4 and 24 h postinjection showed increasing tumor-to-background ratios with time. This was illustrated by the acquisition of PET images showing high tumor-to-normal tissue contrast. This study demonstrates the high affinity of the MeCOSar-PEGx-bombesin conjugates to GRPr. The stability of 64Cu complexes of MeCOSar, the long half-life of 64Cu, and the suitable biodistribution profile of the 64Cu-labeled peptides lead to PET images of high contrast suitable for potential translation into the clinic.

Warthin's tumor of the larynx: a very rare case and systematic review of the literature

BACKGROUND Warthin's tumor or cystadenolymphoma (CAL) is a benign salivary gland tumor occurring almost exclusively in the parotid gland. CALs of other locations are rare. CASE PRESENTATION We report a laryngeal CAL detected in a positron emission tomography/computed tomography (PET/CT) performed for breast cancer follow-up. The tumor was successfully treated by transoral surgery. DISCUSSION Only 14 cases of laryngeal CAL are reported worldwide. These cases confirmed our experience of an uncomplicated and mostly successful transoral resection. CONCLUSION CALs of the larynx are very rare. They are characterized by hypermetabolism in PET/CT. The increasing use of PET/CT investigations in cancer patients could give rise to more incidental findings of CALs at unusual locations such as the larynx.

Dose-painting intensity-modulated proton therapy for intermediate- and high-risk meningioma.

BACKGROUND Newly diagnosed WHO grade II-III or any WHO grade recurrent meningioma exhibit an aggressive behavior and thus are considered as high- or intermediate risk tumors. Given the unsatisfactory rates of disease control and survival after primary or adjuvant radiation therapy, optimization of treatment strategies is needed. We investigated the potential of dose-painting intensity-modulated proton beam-therapy (IMPT) for intermediate- and high-risk meningioma. MATERIAL AND METHODS Imaging data from five patients undergoing proton beam-therapy were used. The dose-painting target was defined using [68]Ga-[1,4,7,10-tetraazacyclododecane tetraacetic acid]- d-Phe(1),Tyr(3)-octreotate ([68]Ga-DOTATATE)-positron emission tomography (PET) in target delineation. IMPT and photon intensity-modulated radiation therapy (IMRT) treatment plans were generated for each patient using an in-house developed treatment planning system (TPS) supporting spot-scanning technology and a commercial TPS, respectively. Doses of 66 Gy (2.2 Gy/fraction) and 54 Gy (1.8 Gy/fraction) were prescribed to the PET-based planning target volume (PTVPET) and the union of PET- and anatomical imaging-based PTV, respectively, in 30 fractions, using simultaneous integrated boost. RESULTS Dose coverage of the PTVsPET was equally good or slightly better in IMPT plans: dose inhomogeneity was 10 ± 3% in the IMPT plans vs. 13 ± 1% in the IMRT plans (p = 0.33). The brain Dmean and brainstem D50 were small in the IMPT plans: 26.5 ± 1.5 Gy(RBE) and 0.002 ± 0.0 Gy(RBE), respectively, vs. 29.5 ± 1.5 Gy (p = 0.001) and 7.5 ± 11.1 Gy (p = 0.02) for the IMRT plans, respectively. The doses delivered to the optic structures were also decreased with IMPT. CONCLUSIONS Dose-painting IMPT is technically feasible using currently available planning tools and resulted in dose conformity of the dose-painted target comparable to IMRT with a significant reduction of radiation dose delivered to the brain, brainstem and optic apparatus. Dose escalation with IMPT may improve tumor control and decrease radiation-induced toxicity.

Detection of significant coronary artery disease by noninvasive anatomical and functional imaging.

BACKGROUND The choice of imaging techniques in patients with suspected coronary artery disease (CAD) varies between countries, regions, and hospitals. This prospective, multicenter, comparative effectiveness study was designed to assess the relative accuracy of commonly used imaging techniques for identifying patients with significant CAD. METHODS AND RESULTS A total of 475 patients with stable chest pain and intermediate likelihood of CAD underwent coronary computed tomographic angiography and stress myocardial perfusion imaging by single photon emission computed tomography or positron emission tomography, and ventricular wall motion imaging by stress echocardiography or cardiac magnetic resonance. If ≥1 test was abnormal, patients underwent invasive coronary angiography. Significant CAD was defined by invasive coronary angiography as >50% stenosis of the left main stem, >70% stenosis in a major coronary vessel, or 30% to 70% stenosis with fractional flow reserve ≤0.8. Significant CAD was present in 29% of patients. In a patient-based analysis, coronary computed tomographic angiography had the highest diagnostic accuracy, the area under the receiver operating characteristics curve being 0.91 (95% confidence interval, 0.88-0.94), sensitivity being 91%, and specificity being 92%. Myocardial perfusion imaging had good diagnostic accuracy (area under the curve, 0.74; confidence interval, 0.69-0.78), sensitivity 74%, and specificity 73%. Wall motion imaging had similar accuracy (area under the curve, 0.70; confidence interval, 0.65-0.75) but lower sensitivity (49%, P<0.001) and higher specificity (92%, P<0.001). The diagnostic accuracy of myocardial perfusion imaging and wall motion imaging were lower than that of coronary computed tomographic angiography (P<0.001). CONCLUSIONS In a multicenter European population of patients with stable chest pain and low prevalence of CAD, coronary computed tomographic angiography is more accurate than noninvasive functional testing for detecting significant CAD defined invasively. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov. Unique identifier: NCT00979199.

Targeted cancer diagnosis with radiolabeled endostatin

Nuclear imaging is used for non-invasive detection, staging and therapeutic monitoring of tumors through the use of radiolabeled probes. Generally, these probes are used for applications in which they provide passive, non-specific information about the target. Therefore, there is a significant need for actively-targeted radioactive probes to provide functional information about the site of interest. This study examined endostatin, an endogenous inhibitor of tumor angiogenesis, which has affinity for tumor vasculature. The major objective of this study was to develop radiolabeled analogues of endostatin through novel chemical and radiochemical syntheses, and to determine their usefulness for tumor imaging using in vitro and in vivo models of vascular, mammary and prostate tumor cells. I hypothesize that this binding will allow for a non-invasive approach to detection of tumor angiogenesis, and such detection can be used for therapeutic monitoring to determine the efficacy of anti-angiogenic therapy. ^ The data showed that endostatin could be successfully conjugated to the bifunctional chelator ethylenedicysteine (EC), and radiolabeled with technetium-99m and gallium-68, providing a unique opportunity to use a single precursor for both nuclear imaging modalities: 99mTc for single photon emission computed tomography and 68Ga for positron emission tomography, respectively. Both radiolabeled analogues showed increased binding as a function of time in human umbilical vein endothelial cells and mammary and prostate tumor cells. Binding could be blocked in a dose-dependent manner by unlabeled endostatin implying the presence of endostatin receptors on both vascular and tumor cells. Animal biodistribution studies demonstrated that both analogues were stable in vivo, showed typical reticuloendothelial and renal excretion and produced favorable absorbed organ doses for application in humans. The imaging data provide evidence that the compounds quantitate tumor volumes with clinically-useful tumor-to-nontumor ratios, and can be used for treatment follow-up to depict changes occurring at the vascular and cellular levels. ^ Two novel endostatin analogues were developed and demonstrated interaction with vascular and tumor cells. Both can be incorporated into existing nuclear imaging platforms allowing for potential wide-spread clinical benefit as well as serving as a diagnostic tool for elucidation of the mechanism of action of endostatin. ^

External assessment of myocardial glucose metabolism with $\sp{18}$F-2 -deoxy-2 -fluoro-D-glucose

Despite the popularity of the positron emitting glucose analog, ($\sp{18}$F) -2-deoxy-2-fluoro-D-glucose (2FDG), for the noninvasive "metabolic imaging" of organs with positron emission tomography (PET), the physiological basis for the tracer has not been tested, and the potential of 2FDG for the rapid kinetic analysis of altered glucose metabolism in the intact heart has not been fully exploited. We, therefore, developed a quantitative method to characterize metabolic changes of myocardial glucose metabolism noninvasively and with high temporal resolution.^ The first objective of the work was to provide direct evidence that the initial steps in the metabolism of 2FDG are the same as for glucose and that 2FDG is retained by the tissue in proportion to the rate of glucose utilization. The second objective was to characterize the kinetic changes in myocardial glucose transport and phosphorylation in response to changes in work load, competing substrates, acute ischemia and reperfusion, and the addition of insulin. To assess changes in myocardial glucose metabolism isolated working rat hearts were perfused with glucose and 2FDG. Tissue uptake of 2FDG and the input function were measured on-line by external detection. The steady state rate of 2FDG phosphorylation was determined by graphical analysis of 2FDG time-activity curves.^ The rate of 2FDG uptake was linear with time and the tracer was retained in its phosphorylated form. Tissue accumulation of 2FDG decreased within seconds with a reduction in work load, in the presence of competing substrates, and during reperfusion after global ischemia. Thus, most interventions known to alter glucose metabolism induced rapid parallel changes in 2FDG uptake. By contrast, insulin caused a significant increase in 2FDG accumulation only in hearts from fasted animals when perfused at a sub-physiological work load. The mechanism for this phenomenon is not known but may be related to the existence of two different glucose transporter systems and/or glycogen metabolism in the myocardial cell.^ It is concluded that (1) 2FDG traces glucose uptake and phosphorylation in the isolated working rat heart; and (2) early and transient kinetic changes in glucose metabolism can be monitored with high temporal resolution with 2FDG and a simple positron coincidence counting system. The new method has revealed transients of myocardial glucose metabolism, which would have remained unnoticed with conventional methods. These transients are not only important for the interpretation of glucose metabolic PET scans, but also provide insights into mechanisms of glucose transport and phosphorylation in heart muscle. ^