The Titrated Mannitol Improved Central [99mTc] Tc TRODAT-1 Uptake in an Animal Model-A Clinically Feasible Application.

[99mTc]Tc TRODAT-1 is a widely used single photon emission tomography (SPECT) radiopharmaceutical in Asian practice for early detection of central dopaminergic disorders. However, its imaging quality remains sub-optimal. To overcome this problem, mannitol, an osmotic agent was used to observe its effect on improving striatal [99mTc]Tc TRODAT-1 uptake in rat brain by titrated human dosages to investigate a clinically feasible way to improve human imaging quality. [99mTc]Tc TRODAT-1 synthesis and quality control were performed as described. Sprague-Dawley rats were used for this study. The animal in vivo nanoSPECT/CT and ex vivo autoradiography were employed to observe and verify the striatal [99mTc]Tc TRODAT-1 uptake in rat brains using clinically equivalent doses (i.e., 0, 1 and 2 mL groups, each n = 5) of mannitol (20% w/v, equivalent to 200 mg/mL) by an intravenous administration. Specific binding ratios (SBRs) were calculated to express the central striatal uptake in different experimental groups. In the NanoSPECT/CT imaging, the highest SBRs of striatal [99mTc]Tc TRODAT-1 were reached at 75-90 min post-injection. The averaged striatal SBRs were 0.85 ± 0.13 (2 mL normal saline, the control group), 0.94 ± 0.26 (1 mL mannitol group) and 1.36 ± 0.12 (2 mL mannitol group, p < 0.01 which were significantly different than the control as well as 1 mL mannitol groups (p < 0.05). The SBRs from ex vivo autoradiography also showed a comparable trend of the striatal [99mTc]Tc TRODAT-1 uptake in the 2 mL, 1 mL mannitol and the control groups (1.76 ± 0.52, 0.91 ± 0.29, and 0.21 ± 0.03, respectively, p < 0.05). No remarkable changes of vital signs were found in the mannitol groups and the controls. Pre-treated mannitol revealed a significant increase of the central striatal [99mTc]Tc TRODAT-1 uptake in a rat model which not only enabled us to perform pre-clinical studies of dopaminergic related disorders but also provided a potential way to further optimize image quality in clinical practice.

Neuroinflammation in Low-Level PM2.5-Exposed Rats Illustrated by PET via an Improved Automated Produced [18F]FEPPA: A Feasibility Study.

Background: [18F]FEPPA is a potent TSPO imaging agent that has been found to be a potential tracer for imaging neuroinflammation. In order to fulfill the demand of this tracer for preclinical and clinical studies, we have developed a one-pot automated synthesis with simplified HPLC purification of this tracer, which was then used for PET imaging of neuroinflammation in fine particulate matter- (PM2.5-) exposed rats. Results: Using this automated synthesis method, the RCY of the [18F]FEPPA was 38 ± 4% (n = 17, EOB) in a synthesis time of 83 ± 8 min from EOB. The radiochemical purity and molar activities were greater than 99% and 209 ± 138 GBq/µmol (EOS, n = 15), respectively. The quality of the [18F]FEPPA synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]FEPPA was stable at 21 ± 2°C for up to 4 hr after the end of synthesis (EOS). Moreover, microPET imaging showed that increased tracer activity of [18F]FEPPA in the brain of PM2.5-exposed rats (n = 6) were higher than that of normal controls (n = 6) and regional-specific. Conclusions: Using the improved semipreparative HPLC purification, [18F]FEPPA has been produced in high quantity, high quality, and high reproducibility and, for the first time, used for PET imaging the effects of PM2.5 in the rat brain. It is ready to be used for imaging inflammation in various clinical or preclinical studies, especially for nearby PET centers without cyclotrons.

Usefulness of estimated pulse wave velocity for identifying prevalent coronary heart disease: findings from a general Chinese population.

BACKGROUND: Aortic stiffness and coronary heart disease (CHD) share a similar spectrum of risk factors; previous studies have identified the association between aortic stiffness and CHD. Recent studies have demonstrated estimated pulse wave velocity (ePWV) as a simple and easy-acquired indicator of aortic stiffness. Our work aims to evaluate the association between ePWV and the prevalence of CHD and assess the value of ePWV for the identification of prevalent CHD. METHODS: The current cross-sectional work included 7012 subjects from rural areas of southeastern China between September 2020 and February 2021. ePWV was calculated from age and mean blood pressure by specific algorithm. RESULTS: The prevalence of CHD in our population was 3.58% (251 patients among 7012 subjects). After adjusting for age, sex, education, income and exercise level, current smoking and drinking status, body mass index, waist circumference, fasting plasma glucose, total cholesterol, high density lipoprotein, estimated glomerular filtration rate and cerebrovascular diseases, each standard deviation increment of ePWV would produce an additional 37.8% risk of prevalent CHD. Moreover, after dividing ePWV into quartiles, the 4th quartile of ePWV showed a significant risk of prevalent CHD (OR (95% CI): 3.567 (1.963-6.479)) when compared with the 1st quartile. Additionally, the subgroup analysis showed the association between ePWV and prevalent CHD was robust to several common risk factors of CHD, including age, sex, body mass index, hypertension, diabetes and reduced estimated glomerular filtration rate. Finally, the area under curve (AUC) displayed an improvement when adding ePWV into common CHD risk factors (0.705 vs. 0.718. P = 0.044). Consistently, net reclassification index (0.436, 95% CI: 0.301-0.571, P < 0.001) and integrated discrimination index (0.004, 95% CI: 0.001-0.006, P = 0.002) demonstrated the value of ePWV to optimize the identification of prevalent CHD in the general population. CONCLUSION: The present analysis implicates the robust association between ePWV, a simple, rapid, and practical marker of aortic stiffness, and prevalent CHD in the general Chinese population. More importantly, the results suggest the value of ePWV as a potential marker to improve the identification of prevalent CHD.

Amitriptyline Accelerates SERT Binding Recovery in a Rat 3,4-Methylenedioxymethamphetamine (MDMA) Model: In Vivo 4-[18F]-ADAM PET Imaging.

Numerous studies have confirmed that 3,4-Methylenedioxymethamphetamine (MDMA) produces long-lasting changes to the density of the serotonin reuptake transporter (SERT). Amitriptyline (AMI) has been shown to exert neuroprotective properties in neuropathologic injury. Here, we used a SERT-specific radionuclide, 4-[18F]-ADAM, to assess the longitudinal alterations in SERT binding and evaluate the synergistic neuroprotective effect of AMI in a rat MDMA model. In response to MDMA treatment regimens, SERT binding was significantly reduced in rat brains. Region-specific recovery rate (normalized to baseline) in the MDMA group at day 14 was 71.29% ± 3.21%, and progressively increased to 90.90% ± 7.63% at day 35. AMI dramatically increased SERT binding in all brain regions, enhancing average ~18% recovery rate at day 14 when compared with the MDMA group. The immunochemical staining revealed that AMI markedly increased the serotonergic fiber density in the cingulate and thalamus after MDMA-induction, and confirmed the PET findings. Using in vivo longitudinal PET imaging, we demonstrated that SERT recovery was positively correlated with the duration of MDMA abstinence, implying that lower SERT densities in MDMA-induced rats reflected neurotoxic effects and were (varied) region-specific and reversible. AMI globally accelerated the recovery rate of SERT binding and increased SERT fiber density with possible neuroprotective effects.

Targeting PSEN1 by lnc-CYP3A43-2/miR-29b-2-5p to Reduce ß Amyloid Plaque Formation and Improve Cognition Function.

Presenilin-1 (PSEN1) is a crucial subunit within the γ-secretase complex and regulates ß-amyloid (Aß) production. Accumulated evidence indicates that n-butylidenephthalide (BP) acts effectively to reduce Aß levels in neuronal cells that are derived from trisomy 21 (Ts21) induced pluripotent stem cells (iPSCs). However, the mechanism underlying this effect remains unclear. This article aims to investigate the possible mechanisms through which BP ameliorates the development of Alzheimer's disease (AD) and verify the effectiveness of BP through animal experiments. Results from RNA microarray analysis showed that BP treatment in Ts21 iPSC-derived neuronal cells reduced long noncoding RNA (lncRNA) CYP3A43-2 levels and increased microRNA (miR)-29b-2-5p levels. Bioinformatics tool prediction analysis, biotin-labeled miR-29b-2-5p pull-down assay, and dual-luciferase reporter assay confirmed a direct negative regulatory effect for miRNA29b-2-5p on lnc-RNA-CYP3A43-2 and PSEN1. Moreover, BP administration improved short-term memory and significantly reduced Aß accumulation in the hippocampus and cortex of 3xTg-AD mice but failed in miR-29b-2-5p mutant mice generated by CRISP/Cas9 technology. In addition, analysis of brain samples from patients with AD showed a decrease in microRNA-29b-2-5p expression in the frontal cortex region. Our results provide evidence that the LncCYP3A43-2/miR29-2-5p/PSEN1 network might be involved in the molecular mechanisms underlying BP-induced Aß reduction.

Automated Synthesis and Initial Evaluation of (4'-Amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase.

Background: Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4'-amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-fluorophenyl)methanone ([18F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation. Methods: An in vitro model, murine microglial BV2 cell line, was used to assess the uptake of [18F]FBAT in response to iNOS induction at the cellular level. In vivo whole-body dynamic PET/MR imaging was acquired in LPS-treated (5 mg/kg) and control mice. Standard uptake value (SUV), total volume of distribution (V t), and area under the curve (AUC) based on the [18F]FBAT PET signals were determined. The expression of iNOS was confirmed by immunohistochemistry (IHC) of brain tissues. Results: At the end of synthesis, the yield of [18F]FBAT was 2.2-3.1% (EOS), radiochemical purity was >99%, and molar radioactivity was 125-137 GBq/µmol. In vitro, [18F]FBAT rapidly and progressively accumulated in murine microglial BV2 cells exposed to LPS; however, [18F]FBAT accumulation was inhibited by aminoguanidine, a selective iNOS inhibitor. In vivo biodistribution studies of [18F]FBAT showed a significant increase in the liver and kidney on LPS-treated mice. At 3 h postinjection of LPS, in vivo, the [18F]FBAT accumulation ratios at 30 min post intravenous (i.v.) radiotracer injection for the whole brain, cortex, cerebellum, and brainstem were 2.16 ± 0.18, 1.53 ± 0.25, 1.41 ± 0.21, and 1.90 ± 0.12, respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC0-30min), total volume of distribution (V t, mL/cm3), and K i (influx rate) of [18F]FBAT were 1.9 ± 0.21- and 1.4 ± 0.22-fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain K i of [18F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC0-30min and V t values in LPS-induced mice. Quantitative analysis of immunohistochemically stained brain sections confirmed iNOS was preferentially upregulated in the cerebellum and cortex of mice injected with LPS. Conclusion: An automated robotic method was established for radiosynthesis of [18F]FBAT, and the preliminary in vitro and in vivo results demonstrated the feasibility of detecting iNOS activity/expression in LPS-treated neuroinflammation by noninvasive imaging with [18F]FBAT PET/MRI.

Functional Dysconnectivity of Frontal Cortex to Striatum Predicts Ketamine Infusion Response in Treatment-Resistant Depression.

BACKGROUND: Frontostriatal disconnectivity plays a crucial role in the pathophysiology of major depressive disorder. However, whether the baseline functional connectivity of the frontostriatal network could predict the treatment outcome of low-dose ketamine infusion remains unknown. METHODS: In total, 48 patients with treatment-resistant depression were randomly divided into 3 treatment groups (a single-dose 40-minute i.v. infusion) as follows: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and saline placebo infusion. Patients were subsequently followed-up for 2 weeks. Resting-state functional magnetic resonance imaging was performed for each patient before infusion administration. In addition, the baseline frontostriatal functional connectivity of patients with treatment-resistant depression was also compared with that of healthy controls. RESULTS: Compared with the healthy controls, patients with treatment-resistant depression had a decreased functional connectivity in the frontostriatal circuits, especially between the right superior frontal cortex and executive region of the striatum and between the right paracingulate cortex and rostral-motor region of the striatum. The baseline hypoconnectivity of the bilateral superior frontal cortex to the executive region of the striatum was associated with a greater reduction of depression symptoms after a single 0.2-mg/kg ketamine infusion. CONCLUSION: Reduced connectivity of the superior frontal cortex to the striatum predicted the response to ketamine infusion among patients with treatment-resistant depression.

Simplified quantification of 13N-ammonia PET myocardial blood flow: A comparative study with the standard compartment model to facilitate clinical use.

BACKGROUND: Short imaging protocol to quantify myocardial blood flow (MBF) and myocardial flow reserve (MFR) may enhance the clinical application of 13N-ammonia cardiac PET. We assessed the flow quantitation of 13N-ammonia PET implementing simple retention model and two-compartment model. METHODS: Fourteen healthy volunteers (HVT) and twenty-three clinical patients received 13N-ammonia PET/CT. The simple retention model used the first 7-minute image to quantify MBF. Global and regional MBF and MFR of the two models were compared. RESULTS: Global and regional MBF and MFR of these two models were highly correlated with mildly inferior correlation in RCA territory (global R2: rest MBF = 0.79, stress MBF = 0.65, MFR = 0.77; regional R2: rest MBF ≥ 0.72, stress MBF ≥ 0.52, MFR ≥ 0.68). There were significant differences for MFR (4.04 ± 0.72, 3.66 ± 0.48, p = .02) and rest MBF (0.69 ± 0.12, 0.78 ± 0.12, p = .02) between the two models in the HVT group. CONCLUSIONS: 13N-ammonia global and regional MBF and MFR from the simple retention model demonstrate strong correlations with that from the two-compartment model. Significant differences of MFR and rest MBF are noted in the HVT group, with a proposed normal reference value for the 13N-ammonia short simple retention protocol.

Effects of the Acute and Chronic Ethanol Intoxication on Acetate Metabolism and Kinetics in the Rat Brain.

BACKGROUND: Ethanol (EtOH) intoxication inhibits glucose transport and decreases overall brain glucose metabolism; however, humans with long-term EtOH consumption were found to have a significant increase in [1-11 C]-acetate uptake in the brain. The relationship between the cause and effect of [1-11 C]-acetate kinetics and acute/chronic EtOH intoxication, however, is still unclear. METHODS: [1-11 C]-acetate positron emission tomography (PET) with dynamic measurement of K1 and k2 rate constants was used to investigate the changes in acetate metabolism in different brain regions of rats with acute or chronic EtOH intoxication. RESULTS: PET imaging demonstrated decreased [1-11 C]-acetate uptake in rat brain with acute EtOH intoxication, but this increased with chronic EtOH intoxication. Tracer uptake rate constant K1 and clearance rate constant k2 were decreased in acutely intoxicated rats. No significant change was noted in K1 and k2 in chronic EtOH intoxication, although 6 of 7 brain regions showed slightly higher k2 than baseline. These results indicate that acute EtOH intoxication accelerated acetate transport and metabolism in the rat brain, whereas chronic EtOH intoxication status showed no significant effect. CONCLUSIONS: In vivo PET study confirmed the modulatory role of EtOH, administered acutely or chronically, in [1-11 C]-acetate kinetics and metabolism in the rat brain. Acute EtOH intoxication may inhibit the transport and metabolism of acetate in the brain, whereas chronic EtOH exposure may lead to the adaptation of the rat brain to EtOH in acetate utilization. [1-11 C]-acetate PET imaging is a feasible approach to study the effect of EtOH on acetate metabolism in rat brain.

SPECT myocardial blood flow quantitation toward clinical use: a comparative study with 13N-Ammonia PET myocardial blood flow quantitation.

OBJECTIVES: The aim of this study was to evaluate the accuracy of myocardial blood flow (MBF) quantitation of 99mTc-Sestamibi (MIBI) single photon emission computed tomography (SPECT) compared with 13N-Ammonia (NH3) position emission tomography (PET) on the same cohorts. BACKGROUND: Recent advances of SPECT technologies have been applied to develop MBF quantitation as a promising tool to diagnose coronary artery disease (CAD) for areas where PET MBF quantitation is not available. However, whether the SPECT approach can achieve the same level of accuracy as the PET approach for clinical use still needs further investigations. METHODS: Twelve healthy volunteers (HVT) and 16 clinical patients with CAD received both MIBI SPECT and NH3 PET flow scans. Dynamic SPECT images acquired with high temporary resolution were fully corrected for physical factors and processed to quantify K1 using the standard compartmental modeling. Human MIBI tracer extraction fraction (EF) was determined by comparing MIBI K1 and NH3 flow on the HVT group and then used to convert flow values from K1 for all subjects. MIBI and NH3 flow values were systematically compared to validate the SPECT approach. RESULTS: The human MIBI EF was determined as [1.0-0.816*exp(-0.267/MBF)]. Global and regional MBF and myocardial flow reserve (MFR) of MIBI SPECT and NH3 PET were highly correlated for all subjects (global R2: MBF = 0.92, MFR = 0.78; regional R2: MBF ≥ 0.88, MFR ≥ 0.71). No significant differences for rest flow, stress flow, and MFR between these two approaches were observed (All p ≥ 0.088). Bland-Altman plots overall revealed small bias between MIBI SPECT and NH3 PET (global: ΔMBF = -0.03Lml/min/g, ΔMFR = 0.07; regional: ΔMBF = -0.07 - 0.06 , ΔMFR = -0.02 - 0.22). CONCLUSIONS: Quantitation with SPECT technologies can be accurate to measure myocardial blood flow as PET quantitation while comprehensive imaging factors of SPECT to derive the variability between these two approaches were fully addressed and corrected.

Abnormal serotonin transporter availability in the brains of adults with conduct disorder.

BACKGROUND/PURPOSE: The aims of the current study were to determine whether patients with conduct disorder (CD) showed an abnormal availability of serotonin reuptake transporter (SERT), and if their hyperkinetic symptoms, impulsivity, and quality of life were correlated with the availability of SERT. METHODS: We recruited 14 drug-naïve patients with CD and eight age-matched healthy controls (HCs). The adult attention-deficit/hyperactivity disorder (ADHD) self-report scale (ASRS), Barrett impulsivity scale (BIS), and the World Health Organization quality of life-brief version (WHOQOL-BREF) scale were administered. Positron emission tomography (PET) of the brain with 4-[18F]-ADAM was arranged for SERT imaging. RESULTS: SERT availability was significantly reduced in the striatum and midbrain of patients with CD. Quality of life and inattention symptoms were also significantly correlated with the availability of SERT in the prefrontal cortex. CONCLUSION: The study suggested that a reduction in the availability of SERT might be associated with CD and could potentially predict poor quality of life or symptoms of inattention for these patients. The implications of our results might be limited to individuals with CD; a future study with a larger sample to validate our preliminary results is warranted.

188Re-Liposome Can Induce Mitochondrial Autophagy and Reverse Drug Resistance for Ovarian Cancer: From Bench Evidence to Preliminary Clinical Proof-of-Concept.

Despite standard treatment, about 70% of ovarian cancer will recur. Cancer stem cells (CSCs) have been implicated in the drug-resistance mechanism. Several drug resistance mechanisms have been proposed, and among these, autophagy plays a crucial role for the maintenance and tumorigenicity of CSCs. Compared to their differentiated counterparts, CSCs have been demonstrated to display a significantly higher level of autophagy flux. Moreover, mitophagy, a specific type of autophagy that selectively degrades excessive or damaged mitochondria, is shown to contribute to cancer progression and recurrence in several types of tumors. Nanomedicine has been shown to tackle the CSCs problem by overcoming drug resistance. In this work, we developed a nanomedicine, 188Re-liposome, which was demonstrated to target autophagy and mitophagy in the tumor microenvironment. Of note, the inhibition of autophagy and mitophagy could lead to significant tumor inhibition in two xenograft animal models. Lastly, we presented two cases of recurrent ovarian cancer, both in drug resistance status that received a level I dose from a phase I clinical trial. Both cases developing drug resistance showed drug sensitivity to 188Re-liposome. These results suggest that inhibition of autophagy and mitophagy by a nanomedicine may be a novel strategy to overcome drug resistance in ovarian cancer.

[Effect of High Hydrostatic Pressure Combined with Temperature on the Antigenicity and Conformation of Tropomyosin Purified from Shrimp].

Foodborne shrimp allergy events have occurred in recent years. To illustrate the mechanism of high hydrostatic pressure technology to change the allergenicity of shrimp, the major allergen tropomyosin was separated and purified from Litopenaeus vannamei, and indentified with matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). The effect of temperature factor under high hydrostatic pressure was measured with indirect ELISA method, CD and fluorescence spectrum. The results showed that the antigenicity of TM protein had an increase after being heated at 35 or 45 ℃ when treated at 300 MPa for 15 minutes, while the antigenicity decreased at 55, 65, and 75 ℃. With the increase of heat temperature, the secondary structure of TM also changed. The mutual transformation happened between the alpha-helix and beta-sheet, beta-turn, and the random coil. The tertiary structure of TM was observed dynamic changes from the extended state to the folded state, and then re-extended state to re-folded state. These results suggested that high hydrostatic pressure combined with temperature could influence the antigenicity of TM by the change of conformation which would be useful as theoretical guidance on developing new methods or technologies for producing hypoallergenic shrimp products.

Radiotherapy did not increase thyroid cancer risk among women with breast cancer: A nationwide population-based cohort study.

The aim of this study was to evaluate whether an increased risk of thyroid cancer exists among women with breast cancer in Taiwan, particularly among those receiving RT. We used data from the National Health Insurance system of Taiwan for the investigation. The breast cancer cohort contained 55,318 women (including 28,187 who received RT and 27,131 who received no RT), each of whom was randomly frequency matched according to age and index year with three women without breast cancer from the general population. Cox's proportion hazards regression analysis was conducted to estimate the effects of breast cancer with or without RT treatment on subsequent thyroid cancer risk. We found that women with breast cancer exhibited a significantly higher risk of subsequent thyroid cancer (adjusted hazard ratio [aHR] = 1.98, 95% confidence interval [CI] = 1.60-2.44). The two groups (with or without RT) in the breast cancer cohort exhibited significantly increased risks. However, in the breast cancer cohort, the risk of thyroid cancer among women who received RT was not significantly higher than that of women who received no RT (aHR = 1.28, 95% CI = 0.90-1.83). Stratified analysis according to age revealed that only younger women with breast cancer (20-54 y) had a significantly higher risk of developing thyroid cancer. This study determined that Taiwanese women with breast cancer had a higher risk of developing thyroid cancer; however, RT seems to not play a crucial role in this possible relationship.

Disproportionate Reduction of Serotonin Transporter May Predict the Response and Adherence to Antidepressants in Patients with Major Depressive Disorder: A Positron Emission Tomography Study with 4-[18F]-ADAM.

BACKGROUND: Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants. METHODS: We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more. RESULTS: Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders. CONCLUSIONS: The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD.

(131)I treatment for thyroid cancer and the risk of developing salivary and lacrimal gland dysfunction and a second primary malignancy: a nationwide population-based cohort study.

OBJECTIVE: The aim of this study was to determine the prevalence of salivary and lacrimal gland dysfunction and a second primary malignancy in patients from Taiwan with thyroid cancer after radioiodine therapy. METHODS: This nationwide population-based cohort study was based on data obtained from the Taiwan National Health Insurance Database from 2000 to 2011. A total of 1,834 thyroid cancer patients treated with (131)I therapy and 1,834 controls (thyroid cancer without (131)I therapy) selected by 1:1 matching on a propensity score were enrolled. The cumulative (131)I dose in each patient was calculated. A Cox proportional hazards model was applied to estimate the effect of radiation from the (131)I therapy on the risk of salivary and lacrimal gland impairment as well as second primary malignancies in terms of hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In patients treated with (131)I therapy and in controls, the incidence rates of salivary gland dysfunction were 6.76 and 1.01 per 10,000 person-years, respectively (HR 6.81, 95% CI 0.74 - 55.3), the incidence rates of keratoconjunctivitis sicca (KCS) were 13.6 and 16.3 per 10,000 person-years, respectively (HR 0.84, 95% CI 0.41 - 1.73), and the incidence rates of second primary malignancy were 76.7 and 62.4 per 10,000 person-years, respectively (HR 1.23, 95% CI 0.88 - 1.72). The risk of salivary secretion impairment significantly increased with increasing administered doses (HR 14.3, 95% CI 1.73 - 119.0). However, there was no increase in the incidence of KCS or secondary cancer in patients treated with higher doses. CONCLUSION: (131)I therapy insignificantly increased the risk of salivary gland dysfunction and second primary malignancy. In patients with higher cumulative doses, an increase in the incidence of salivary gland dysfunction was observed. By contrast, we did not find an association between (131)I treatment and KCS development.

Incongruent reduction of serotonin transporter associated with suicide attempts in patients with major depressive disorder: a positron emission tomography study with 4-[18F]-ADAM.

BACKGROUND: Much evidence supports the role of the serotonin transporter (SERT) in the pathophysiology and pharmacotherapy of major depressive disorder (MDD) and suicidal behaviors. METHODS: In this study, we recruited 17 antidepressant-naïve patients with MDD and 17 age- and gender-matched healthy controls. SERT availability was measured in vivo with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) positron emission tomography (PET) imaging. The 21-item Hamilton Depression Rating Scale (HDRS) and Beck Scale for Suicide Ideation were used to assess the severity of depression and the intent of suicide ideation prior to PET imaging. All subjects with MDD were in a current state of depression with HDRS scores ≧18. Subjects who attempted suicide within two weeks of the study onset were recruited in the depressed suicidal group (n = 8). Subjects with MDD who denied any prior suicide attempt were recruited into the depressed non-suicidal group (n = 9). RESULTS: A significant reduction of SERT availability in the midbrain, thalamus, and striatum was noted in the MDD group relative to the control group (Bonferroni-adjusted p-value < 0.05). Moreover, this effect was more pronounced in the depressed suicidal group compared to the control group (Bonferroni-adjusted p-value < 0.01). Relative to both the depressed non-suicidal and control groups, the depressed suicidal group showed an increased prefrontal cortex (PFC)/midbrain SERT binding ratio (Bonferroni-adjusted p-value < 0.01). CONCLUSIONS: This study suggests an incongruent reduction of PFC SERT binding relative to the midbrain might discriminate between depressed suicide attempters and non-attempters in patients with MDD and may be involved in the pathophysiology of suicide behaviors.

Quantitation of myocardial blood flow and myocardial flow reserve with 99mTc-sestamibi dynamic SPECT/CT to enhance detection of coronary artery disease.

PURPOSE: Conventional dual-head single photon emission computed tomography (SPECT)/CT systems capable of fast dynamic SPECT (DySPECT) imaging have a potential for flow quantitation. This study introduced a new method to quantify myocardial blood flow (MBF) and myocardial flow reserve (MFR) with DySPECT scan and evaluated the diagnostic performance of detecting coronary artery disease (CAD) compared with perfusion using invasive coronary angiography (CAG) as the reference standard. METHODS: This study included 21 patients with suspected or known CAD who had received DySPECT, ECG-gated SPECT (GSPECT), and CAG (13 with ≥ 50% stenosis in any vessel; non-CAD group: 8 with patent arteries or < 50% stenosis). DySPECT and GSPECT scans were performed on a widely used dual-head SPECT/CT scanner. The DySPECT imaging protocol utilized 12-min multiple back-and-forth gantry rotations during injections of (99m)Tc-sestamibi (MIBI) tracer at rest or dipyridamole-stress stages. DySPECT images were reconstructed with full physical corrections and converted to the physical unit of becquerels per milliliter. Stress MBF (SMBF), rest MBF (RMBF), and MFR were quantified by a one-tissue compartment flow model using time-activity curves derived from DySPECT images. Perfusion images were processed for GSPECT scan and interpreted to obtain summed stress score (SSS) and summed difference score (SDS). Receiver-operating characteristic (ROC) analyses were conducted to evaluate the diagnostic performance of flow and perfusion. RESULTS: Using the criteria of ≥ 50% stenosis as positive CAD, areas under the ROC curve (AUCs) of flow assessment were overall significantly greater than those of perfusion. For patient-based analysis, AUCs for MFR, SMBF, SSS, and SDS were 0.91 ± 0.07, 0.86 ± 0.09, 0.64 ± 0.12, and 0.59 ± 0.13. For vessel-based analysis, AUCs for MFR, SMBF, SSS, and SDS were 0.81 ± 0.05, 0.76 ± 0.06, 0.62 ± 0.07, and 0.56 ± 0.08, respectively. CONCLUSION: The preliminary data suggest that MBF quantitation with a conventional SPECT/CT system and the flow quantitation method is a clinically effective approach to enhance CAD detection.

Relation of early post-stress left ventricular dyssynchrony and the extent of angiographic coronary artery disease.

BACKGROUND: Previous studies showed different dyssynchrony patterns between ischemic and normal myocardium at early post-stress using Tl-201 gated SPECT myocardial perfusion imaging (MPI). The aim of this study was to assess the relation of stress-induced dyssynchrony and the extent of angiographic coronary artery disease (CAD). METHODS AND RESULTS: The MPI images of 144 patients were retrospectively analyzed. With ≥70% stenosis as the criteria of CAD, 57 had no CAD, 32 had 1-vessel disease, 36 had 2-vessel disease, and 19 had 3-vessel disease, respectively. LV global and territorial dyssynchrony parameters were measured by the phase analysis from stress/rest Tl-201 SPECT MPI and compared between stress and rest among the patient groups. The patients with multi-vessel CAD had significantly more global dyssynchrony than the patients without ≥70% stenosis at stress. The patients with multi-vessel CAD showed significantly more global and territorial dyssynchrony on stress images than on rest. More patients with 3-vessel CAD were correctly classified as multi-vessel disease, when combining both visual interpretation and dyssynchrony assessment. CONCLUSION: The patients with multi-vessel CAD had significantly more global and territorial dyssynchrony at early post-stress than at rest. Such quantitative measures of myocardial stunning may assist in the diagnosis of multi-vessel CAD.