Faculty Bibliography

INTRODUCTION/UNASSIGNED:PET imaging. METHODS/UNASSIGNED:F]SFB in acetonitrile/0.1 M borate buffer solution (final pH ~ 8.5) with an incubation of 20 min at room temperature, followed by purification on a PD MiniTrap G-25 size exclusion gravity column. RESULTS/UNASSIGNED:F]SFB and bispecific antibodies showed a 65%-83% conversion efficiency with radiochemical purities of 95%-99% by radio-TLC. CONCLUSIONS/UNASSIGNED:PET imaging.

Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [¹¹C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [¹¹C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m²) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.

PURPOSE/OBJECTIVE:Roux-en-Y gastric bypass (RYGB) surgery is currently the most efficient treatment to achieve long-term weight loss in individuals with severe obesity. This is largely attributed to marked reductions in food intake mediated in part by changes in gut-brain communication. Here, we investigated for the first time whether weight loss after RYGB is associated with alterations in central noradrenaline (NA) neurotransmission. MATERIALS AND METHODS/METHODS:C]O-methylreboxetine and positron emission tomography to estimate NA transporter (NAT) availability before and 6 months after surgery. NAT distribution volume ratios (DVR) were calculated by volume-of-interest analysis and the two-parameter multilinear reference tissue model (reference region: occipital cortex). RESULTS:(p < 0.001) from baseline. This was paralleled by a significant reduction in DVR in the dorsolateral prefrontal cortex (pre-surgery 1.12 ± 0.04 vs. post-surgery 1.07 ± 0.04; p = 0.019) and a general tendency towards reduced DVR throughout the brain. Furthermore, we found a strong positive correlation between pre-surgery DVR in hypothalamus and the change in BMI (r = 0.78; p = 0.01). CONCLUSION/CONCLUSIONS:Reductions in BMI after RYGB surgery are associated with NAT availability in brain regions responsible for decision-making and homeostasis. However, these results need further validation in larger cohorts, to assess whether brain NAT availability could prognosticate the outcome of RYGB on BMI.

OBJECTIVE:F-DA) to assess intraneuronal vesicular storage in the same subjects. METHODS:F-DA scanning for 30 minutes (same dynamic imaging sequence) after 3-minute infusions of the tracers on separate days. RESULTS:C ratios in septal myocardium were lower in the PAF than control group. INTERPRETATION/CONCLUSIONS:PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves.

Brown adipose tissue (BAT) is responsible for adaptive thermogenesis. We previously showed that genetic deficiency of receptor for advanced glycation end products (RAGE) prevented the effects of high-fat diet (HFD). This study was to compare BAT activity in RAGE knock out (Ager^-/-, RKO) and wild-type (WT) mice after treated with HFD or LFD. [¹⁸F]FDG PET-CT imaging under identical cold-stimulated conditions and mean standard uptake values (SUV_mean), ratio of SUV_iBAT/SUV_muscle (SUVR, muscle as the reference region) and percentage ID/g were used for BAT quantification. The results showed that [¹⁸F]FDG uptake (e.g., SUVR) in WT-HFD mice was significantly reduced (three-fold) as compared to that in WT-LFD (1.40 +/- 0.07 and 4.03 +/- 0.38; P = 0.004). In contrast, BAT activity in RKO mice was not significantly affected by HFD, with SUVR_RKO-LFD: 2.14 +/- 0.10 and SUVR_RKO-LFD: 1.52 +/- 0.13 (P = 0.3). The uptake in WT-LFD was almost double of that in RKO-LFD (P = 0.004); however, there was no significant difference between RKO-HFD and WT-HFD mice (P = 0.3). These results, corroborating our previous findings on the measurement of mRNA transcripts for UCP1 in the BAT, suggest that RAGE may contribute to altered energy expenditure and provide a protective effect against HFD by Ager deletion (Ager ^-/-).

The central noradrenaline (NA) stress-response network co-mediates hypothalamic-pituitary-adrenal (HPA) axis activation and arginine-vasopressin (AVP) release. Dysregulation of these systems contributes to stress-related diseases such as human obesity, but their interrelation remains unclear. The study was aimed to test for the first time in vivo whether central noradrenergic activity quantitatively indexed by the availability of the presynaptic NA transporter (NAT) is associated with HPA axis responsiveness as measured with the combined dexamethasone suppression/corticotropin releasing hormone stimulation (dex/CRH) test and copeptin as a surrogate marker of the serum AVP tone in highly obese, otherwise, healthy individuals compared to age- and sex-matched non-obese, healthy controls. In order to assess central NAT availability, positron emission tomography (PET) was applied using the NAT-selective radiotracer S,S-[¹¹C]O-methylreboxetine (MRB) and correlated with curve indicators derived from the dex/CRH test (maximum, MAX, and area under the curve, AUC, for cortisol and adrenocorticotropic hormone, ACTH) as well as with copeptin. In non-obese controls, positive correlations were found between the NAT distribution volume ratios (DVR) of the orbitofrontal cortex (OFC) and the amygdala with the HPA response (OFC: ACTH_MAX r = 0.87, p = .001; cortisol_MAX r = 0.86, p = .002; amygdala: ACTH_MAX r = 0.86, p = .002; cortisol_MAX r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisol_MAX, r = -0.66, p = .04) and with copeptin (r = -0.71, p = .02). This association of central NAT availability with HPA axis responsiveness and copeptin suggests a mechanistic interaction between noradrenergic transmission with HPA axis activity and the serum AVP system that differs between non-obese individuals with prefrontal-limbic involvement and obesity with a hypothalamic-centered relationship. Whether the latter finding contributes to obesogenic behavior needs to be further explored.

Background: Randomized-trial data on the long-term effects on infants' physical growth and neurodevelopment of the use of tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) mothers are lacking. Methods: All 180 infants who completed the IN-US174-0174 study were offered participation in a long-term follow-up (LTFU) study.1 They were from CHB mothers who were randomly assigned (1:1 ratio) to receive usual care without antiviral therapy or to receive TDF from 30 to 32 weeks of gestation until postpartum week 4. For the LTFU study, infants were assessed at the ages of 72, 120 and 192 weeks for growth and neurodevelopment with Bayley-III measurement. Their bone mineral density (BMD) was measured at week 192. The neurodevelopmental delay was defined by cognitive and language composite scores <85 (1 SD below the mean of 100).2 These parameters were compared between the TDF-exposed and TDFunexposed groups. Results: Among 180 infants completed in the initial study, 176 (98%) participated in the LTFU study and 144 (82%) completed the LTFU. In the TDF-exposed group, the mean (+/-SD) duration of fetal exposure to TDF was 8.57+/-0.53 weeks. The gestational age, delivery mode, weight, height, and Apgar score at birth were similar in the two groups. At week 192, there was no significant difference in the pre-specified outcomes between groups including head circumference, height, BMD, cognitive, social-emotional, and adaptive behavior measurements between groups. There was no neurodevelopmental delay in the cohort. In the TDF-exposed group, children had significantly higher motorcomposite scores (146.46+/-6.39 vs 142.88+/-9.54; p=0.009) and boys had significantly lower mean body weight (18.48+/-2.35kg vs 19.84+/-3.46kg; p= 0.029). However, the boys' mean body weight in the TDF-exposed group was significantly higher than that of the national Chinese reference value of 4-year-old boys (18.48+/-2.35kg vs 16.64+/-1.89; p=0.010).3Conclusion: Among infants with fetal exposure to TDF, the physical growth, BMD, and neurodevelopment were similar to those without the exposure and within the normal range of Chinese reference values during 192-week follow-up. Our data support the safety of using TDF during the third trimester in mothers with CHB. Acknowledgment: (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01488526.) References: Pan CQ, Duan Z, Dai E, et al. Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load. N Engl J Med 2016;374:2324-34. Johnson S, Moore T, Marlow N. Using the Bayley-III to assess neurodevelopmental delay: which cut-off should be used? Pediatr Res 2014;75:670-4. Li H. [Growth standardized values and curves based on weight, length/ height and head circumference for Chinese children under 7 years of age]. Zhonghua Er Ke Za Zhi 2009;47:173-8. (Table Presented)

PURPOSE/OBJECTIVE:Although the mechanisms by which the central noradrenaline (NA) system influences appetite and controls energy balance are quite well understood, its relationship to changes in body weight remains largely unknown. The main goal of this study was to further clarify whether the brain NA system is a stable trait or whether it can be altered by dietary intervention. METHODS:C]O-methylreboxetine (MRB) before and 6 months after dietary intervention. RESULTS: = 0.80; p < 0.0001). No changes were observed in non-obese controls. CONCLUSION/CONCLUSIONS:These first longitudinal interventional data on NAT availability in highly obese individuals indicate that the central NA system is modifiable. Our findings suggest that NAT availability before intervention could help predict the amount and success of weight loss in obese individuals and help adjust treatment options individually by allowing prediction of the benefit of a dietary intervention.

Context/UNASSIGNED:Hypoglycemia, one of the major factors limiting optimal glycemic control in insulin-treated diabetic patients, elicits a brain response to restore normoglycemia by activating counterregulation. Animal data indicate that local release of norepinephrine in the hypothalamus is important for triggering hypoglycemia-induced counterregulatory (CR) hormonal responses. Objective/UNASSIGNED:To examine the potential role of brain noradrenergic activation in humans during hypoglycemia. Design/UNASSIGNED:A hyperinsulinemic-hypoglycemic clamp was performed in conjunction with PET imaging. Participants/UNASSIGNED:Nine lean healthy volunteers were studied during the hyperinsulinemic-hypoglycemic clamp. Design/UNASSIGNED:Participants received intravenous injections of (S,S)-[11C]O-methylreboxetine, [11C]MRB, a highly selective norepinephrine transporter (NET) ligand, at baseline and during hypoglycemia. Results/UNASSIGNED:Hypoglycemia increased plasma epinephrine, glucagon, cortisol and growth hormone, and decreased [11C]MRB binding potential (BPND) by 24 ± 12% in the raphe nucleus (P<0.01). In contrast, changes in [11C]MRB (BPND) in the hypothalamus positively correlated with increments in epinephrine and glucagon levels and negatively correlated with glucose infusion rate (all P<0.05). Furthermore, in rat hypothalamus studies, hypoglycemia induced NET translocation from the cytosol to the plasma membrane. Conclusions/UNASSIGNED:Insulin-induced hypoglycemia initiated a complex brain noradrenergic response in humans. Raphe nuclei, a region involved in regulating autonomic output, motor activity and hunger, was observed to have increased noradrenergic activity, while the hypothalamus showed a NET-binding pattern that was associated with the individual's CR response magnitude. These findings suggest that noradrenergic output most likely is important for modulating brain responses to hypoglycemia in humans.

Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder (MDD) and bipolar disorder (BD), but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter (NET) which might account for its therapeutic efficacy. Method: In this study, we used positron emission tomography (PET) with 11C-MRB to estimate NET density and assess the relationship between NET occupancy by quetiapine XR and improvement in depression in patients with MDD (n=5) and BD (n=5). After the baseline PET scan, patients were treated with quetiapine XR with a target dose of 150 mg in MDD and 300 mg in BD. Patients had a second PET scan at the end of week 2, and a final scan at week 7. Results: NET density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and NET occupancy in locus ceruleus at week 2. The NET occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% NET occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% NET occupancy was 36.8 microg/L. Conclusion: These data provide preliminary support for the hypothesis that NET occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.