Faculty Bibliography

Introduction: The brain neurotransmitters serotonin and noradrenaline are both implicated in the regulation of appetite and energy balance. Alterations of these systems, i.e. in key areas of feeding control such as the hypothalamus or the dorsal raphe nucleus (DRN), lead to eating disorders and obesity; however, the underlying mechanisms are not fully explored yet. Here, we propose a model of body mass index (BMI)-related changes of SERT and NAT together with post-interventional (diet, Roux-Y-gastric bypass surgery, RYGB) data.
Method(s): PET was performed in non-depressed individuals with obesity twice prior and after 6 months following dietary or RYGB intervention using SERT-selective ¹¹C-DASB (n=30 diet, BMI 41.3+/-4.9 kg/m² , age 37+/-10 years, 22 females; n=13 RYGB, BMI 45.0+/-3.9 kg/m² , age 45+/-12 years, 7 females) or ¹¹C-MRB (n=10 diet, BMI 42.4+/-3.6 kg/m² , age 34+/-9 years, 4 females; n=9 RYGB, BMI 46.9+/-4.9 kg/m² , age 46+/-13 years, 7 females) to obtain SERT/NAT binding potential BP (applying multilinear reference tissue modelling with two parameters) of the hypothalamus and the DRN (individually defined on coregistered MRI) as the primary outcome measure compared with the baseline and 6-months follow-up data of normal-weight (NW), healthy controls (n=15 ¹¹C-DASB, BMI 22.5+/-2.5 kg/m² , age 36+/-7 years, 10 females; n=10 ¹¹C-MRB, BMI 23.9+/-2.5 kg/m² , age 33+/-10 years, 4 females).
Result(s): At baseline, SERT BP in the DRN was highest in the diet group (NW 2.99+/-0.7 vs. diet 3.63+/-0.9 vs. RYGB 3.15+/-2.0; ANOVA p=0.19). Post-diet data showed no changes in SERT BP (DRN) while average change of BMI was modest (mean -2.8 kg/m² or -6.8%; p=0.01). SERT BP increased after RYGB (follow-up: 3.45+/-0.2; p=0.1) together with a highly significant decrease of BMI (mean -12.4 kg/m² or -26.7%; p<0.0001). NAT BP in the hypothalamus decreased with increasing BMI (NW 0.53+/-0.1 vs. diet 0.43+/-0.2 vs. RYGB 0.44+/-0.1, ANOVA p=0.26) forming a U-shaped relationship between NAT and BMI (R =0.2; Figure). As predicted from the baseline measures, NAT BP increased slightly after diet (0.44+/-0.2; n.s.) and decreased after RYGB (follow-up: 0.30+/-0.2; p=0.15; Figure). Both BMI and BP remained stable in NW.
Conclusion(s): Taken together, our findings suggest a dynamic relationship between both monoamine systems and markers of obesity during the development of obesity, possibly based on tonus shifts, processes of neuroplasticity, or different endophenotypes in individuals with moderate obesity and severe obesity. Specifically, our data indicate a model of curvilinear and inverse curvilinear relationship of the respective transporters related to the BMI in regions relevant for feeding control. If confirmed in larger series and further related to the individual endocrine, metabolic and behavioral factors, such findings may point to the use of one or both transporters as PET biomarker for treatment decision, course monitoring and for the prediction of treatment success

Classically derived from toad venom, bufadienolides are a group of cardioactive steroids with properties similar to digoxin. Some traditional Chinese medications, including several aphrodisiacs, contain bufadienolides. Owing to their physiologic similarities to digoxin, bufadienolides have been shown to produce a toxic profile similar to that of digoxin and there have been multiple case reports of the use of these aphrodisiacs resulting in death. This report will describe a case that illustrates the electrophysiologic similarities between bufadienolide toxicity and digoxin toxicity as well as the treatment of bufadienolide toxicity.

Ziel/Aim: Obesity is one of the largest preventable diseases worldwide with still increasing prevalence. Yet the pathophysiology behind the neurobiology of obesity is not fully understood. Treatment success varies interindividually and an adjusted treatment is of urgent need. Neuroimaging studies have revealed structural and functional changes of the central norepinephrine system (NE) in brain regions, especially the limbic system, associated with obesity. It was our aim to investigate if these changes might hand us a prediction marker for weight loss success in subsequent dietary intervention. Methodik/Methods: 10 obese non-depressed, metabolically healthy volunteers (BMI>35; 42.4+/-3.7kg/m2, age 34+/-9yrs, 4 women) underwent PET with the NE-transporter (NET)-selective radiotracer (S,S)-[11C]O-methylreboxetine (MRB) before dietary intervention. A multi-linear reference tissue model was used to obtain NET binding potential (BPND). NET availability at baseline (BS) in distinct brain areas was compared with the amount of weight loss after six months of dieting by voxel-wise regression analysis (SPM). Correlation coefficients were extracted from significant clusters by volume-of-in - terest analysis, defined by a SPM threshold of p<0.005 (uncorr.). Ergebnisse/Results: Weight loss of obese patients by

OBJECTIVES: The neurobiological mechanisms linking obesity to emotional distress remain largely undiscovered. METHODS: In this pilot study, we combined positron emission tomography, using the norepinephrine transporter (NET) tracer [11C]-O-methylreboxetine, with functional connectivity magnetic resonance imaging, the Beck depression inventory (BDI), and the impact of weight on quality of life-Lite questionnaire (IWQOL-Lite), to investigate the role of norepinephrine in the severity of depression (BDI), as well as in the loss of emotional well-being with body weight (IWQOL-Lite). RESULTS: In a small group of lean-to-morbidly obese individuals (n=20), we show that an increased body mass index (BMI) is related to a lowered NET availability within the hypothalamus, known as the brain's homeostatic control site. The hypothalamus displayed a strengthened connectivity in relation to the individual hypothalamic NET availability to the anterior insula/frontal operculum, as well as the medial orbitofrontal cortex, assumed to host the primary and secondary gustatory cortex, respectively (n=19). The resting-state activity in these two regions was correlated positively to the BMI and IWQOL-Lite scores, but not to the BDI, suggesting that the higher the resting-state activity in these regions, and hence the higher the BMI, the stronger the negative impact of the body weight on the individual's emotional well-being was. CONCLUSIONS: This pilot study suggests that the loss in emotional well-being with weight is embedded within the central norepinephrine network.International Journal of Obesity advance online publication, 1 December 2015; doi:10.1038/ijo.2015.216.

Objectives Neuroimaging studies have revealed structural and functional changes of the central norepinephrine system (NE) in brain regions associated both with obesity and neuromodulatory actions of the NE system that promote eating disorders. The therapeutic targets to suppress appetite and reduce weight for example by pharmacological intervention are the presynaptic NE transporters (NET). The mechanism, however, which relate NET activity with feeding remain unknown. The main goal of this study was to determine whether NET is a stable trait of human obesity or might be altered through treatment-as-usual, in particular dietary intervention, consequently results out of obesity. Therefore we compare cerebral PET data reflecting regional NET availability in highly obese individuals before and after 6 months of dietary intervention together with behavioral scores assessing emotional eating as well as impulsive and effort control (FEV-II, BIS-11, ATQ). Methods 10 obese non-depressed volunteers (BMI>35; 42.4+/-3.7kg/m², age 34+/-9yrs, 4) underwent PET with the NET-selective (S,S)-[11C]O-methylreboxetine (MRB), MRI and BIS-11, FEV-II, ATQ before and 6 months after dietary intervention, applying atlas-derived volume-of-interest image analysis using a multi-linear reference tissue model to obtain NET binding potential (BPnd). NET availability in distinct brain areas from 10 obese patients were compared with those of 10 matched non-obese volunteers (BMI 23.9+/-2.5kg/m², age 33+/-10yrs, 4). Results Neither significant BMI changes nor a correlation between changes in BMI with BPnd changes over time were found in the control group (delta-BMI -0.2+/-5.9%). In obese patients, change in BMI (-3.3+/-5.3%) was significantly correlated with the NET availability of the insula (R=-0.67, p=0.033) and of the hippocampus (R=-0.69, p=0.029) and increased in obese individuals following completion of intervention (e.g. insula delta BPnd 0.02+/-0.11). NET changes in the insula were related to changes in FEV-II (R=0.71; p=0.02), ATQ (R= -0.67; p=0.03) and BIS-11 total score (R=0.62; p=0.06). Furthermore we found a correlation between changes in the BMI with changes in these behavioral scales (BIS-11 total: R= 0.76; p= 0.01; FEV-II: R= 0.63; p= 0.05; ATQ: R= -0.77; p=0.009). Conclusions During 6-months follow up of dietary intervention in highly obese individuals, NET changes predominantly in the insula indicate the involvement of sensory-interoceptive functions accompanying regimes for treating obesity. These changes are closely related to improvement in eating behaviors, which suggests a lower emotionally driven and less impulsive food intake and may point to a more balanced NE tone after successful treatment. However, BMI-related NET changes in the hippocampus did not have a behavioral correlate so far

Norepinephrine plays a central role in emotional regulation. Further, the predisposition and maintenance of eating disorders have been linked to the central NET system. However, the relationship between emotional eating and NET availability has not yet been investigated. Therefore we investigated the NET status in heavily obese patients with regard to emotional eating, expressed emotion and external eating. We studied 10 obese, non-depressive subjects (OB, body mass index (BMI) 42.4+3.7 kg/m2, age 34.4+9.0 years, 4 female) and 10 control subjects (HC, BMI 23.9+2.5 kg/m2, age 33.3+10 years, 4 female) with C-11 methylreboxetine (MRB) and PET. The NET binding potential (BP) were obtained by individual MR-based volume-of-interest (VOI) analysis (PMOD 3.4). Prior to scanning, participants completed the Difficulties in Emotion Regulation Scale (DERS); the Brief Dyadic Scale of Expressed Emotion (BDSEE) Criticism (CC); emotional over involvement (EOI); and the Dutch Eating Behavior Questionnaire's (DEBQ) External Eating (EE) subscale. The BDSEE-CC differed significantly between OB and HC (p=0.03) whereas there was no group differences regarding the remaining psychometrical total and/or subscale scores or the BP in the distinct brain areas. BP was associated with the BDSEE-CC score in HC, but not in OB in the thalamus (HC, right thalamus: r=0.77; p=0.01; HC, left thalamus: r=0.78; p=0.01). In contrast, DERS total score correlates significantly in OB but not in HC with BP in the thalamic regions (OB, DERS total score, left thalamus: r=0.69; p=0.04) and reward-related regions such as nucleus accumbens (OB: r=-0.67; p=0.05). DEBQ-EE subscale again showed thalamic involvement in OB (r=0.81; p<0.001). The negative effect criticism (BDSEE-CC) was found to be the only psychometrical subscore that significantly differed between OB and HC. The association of central NET availability and emotional eating scores point to the suggestion that NE dysfunction in brain regions crucial for information processing might !

BACKGROUND: -While numerous SNPs in Chromosome 9p21 have been associated with coronary artery disease (CAD) and incident MI in Caucasians, there are limited and conflicting reports on the association of this locus with prognosis in Caucasians with existing CAD and no reports in blacks or Hispanics. We investigated the hypothesis that 9p21 polymorphisms are associated with increased risk for adverse cardiovascular outcomes in patients with documented CAD. METHODS AND RESULTS: -We studied the association of 155 chromosome 9p21 SNPs with adverse outcomes among hypertensive CAD patients of multiple races/ethnicities in INVEST GENES (the INternational VErapamil SR Trandolapril STudy GENetic Substudy, n= 1,460, n = 5,979 for 2 SNPs) and with replication testing of 4 SNPs in the INFORM (INvestigation oF Outcomes from acute coronary syndRoMe; n=714) study of acute coronary syndrome (ACS) patients. In INVEST, the haplotype comprised of the risk allele for the widely reported 9p21 SNPs was associated with better prognosis in Caucasians (OR, 95% CI: 0.72, 0.57-0.92, p = 0.0085) but not blacks (1.21, 0.68-1.24, p = 0.52) or Hispanics (0.96, 0.65-1.44, p=0.86). A less commonly reported LD block was associated with worse prognosis in INVEST among both Caucasians (OR=1.52 (1.20-1.93), p = 0.0006) and African Americans (OR = 4.11 (1.55-10.88), p = 0.004). CONCLUSIONS: -Our findings suggest previously reported chromosome 9p21 SNPs, which predict incident CAD, are not associated with higher risk for adverse outcomes in patients with established CAD. The less commonly reported LD block warrants further investigation. Clinical Trial Registration Information-http://clinicaltrials.gov/ct2/show/NCT00133692. ClinicalTrials.gov; Identifier: NCT00133692

CONTEXT: Hypertension guidelines advocate treating systolic blood pressure (BP) to less than 130 mm Hg for patients with diabetes mellitus; however, data are lacking for the growing population who also have coronary artery disease (CAD). OBJECTIVE: To determine the association of systolic BP control achieved and adverse cardiovascular outcomes in a cohort of patients with diabetes and CAD. DESIGN, SETTING, AND PATIENTS: Observational subgroup analysis of 6400 of the 22,576 participants in the International Verapamil SR-Trandolapril Study (INVEST). For this analysis, participants were at least 50 years old and had diabetes and CAD. Participants were recruited between September 1997 and December 2000 from 862 sites in 14 countries and were followed up through March 2003 with an extended follow-up through August 2008 through the National Death Index for US participants. INTERVENTION: Patients received first-line treatment of either a calcium antagonist or beta-blocker followed by angiotensin-converting enzyme inhibitor, a diuretic, or both to achieve systolic BP of less than 130 and diastolic BP of less than 85 mm Hg. Patients were categorized as having tight control if they could maintain their systolic BP at less than 130 mm Hg; usual control if it ranged from 130 mm Hg to less than 140 mm Hg; and uncontrolled if it was 140 mm Hg or higher. MAIN OUTCOME MEASURES: Adverse cardiovascular outcomes, including the primary outcomes which was the first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: During 16,893 patient-years of follow-up, 286 patients (12.7%) who maintained tight control, 249 (12.6%) who had usual control, and 431 (19.8%) who had uncontrolled systolic BP experienced a primary outcome event. Patients in the usual-control group had a cardiovascular event rate of 12.6% vs a 19.8% event rate for those in the uncontrolled group (adjusted hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.25-1.71; P < .001). However, little difference existed between those with usual control and those with tight control. Their respective event rates were 12.6% vs 12.7% (adjusted HR, 1.11; 95% CI, 0.93-1.32; P = .24). The all-cause mortality rate was 11.0% in the tight-control group vs 10.2% in the usual-control group (adjusted HR, 1.20; 95% CI, 0.99-1.45; P = .06); however, when extended follow-up was included, risk of all-cause mortality was 22.8% in the tight control vs 21.8% in the usual control group (adjusted HR, 1.15; 95% CI, 1.01-1.32; P = .04). CONCLUSION: Tight control of systolic BP among patients with diabetes and CAD was not associated with improved cardiovascular outcomes compared with usual control. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00133692