Faculty Bibliography

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.

PURPOSE: LRRK2 (leucine-rich repeat kinase 2) has recently been proven to be a promising drug target for Parkinson's disease (PD) due to an apparent enhanced activity caused by mutations associated with familial PD. To date, there have been no reports in which a LRRK2 inhibitor has been radiolabeled and used for in in vitro or in vivo studies of LRRK2. In the present study, we radiolabeled the LRRK2 ligand, LRRK-IN-1, for the purposes of performing in vitro (IC50, K d , B max, autoradiography) and in vivo (biodistribution, and blocking experiments) evaluations in rodents and human striatum tissues. PROCEDURES: [3H]LRRK2-IN-1 was prepared with high radiochemical purity (>99 %) and a specific activity of 41 Ci/mmol via tritium/hydrogen (T/H) exchange using Crabtree's catalyst. For IC50, K d , and B max determination, LRRK2-IN-1 was used as a competing drug for nonspecific binding assessment. The specific binding of the tracer was further evaluated via an in vivo blocking study in mice with a potent LRRK2 inhibitor, Pf-06447475. RESULTS: In vitro binding studies demonstrated a saturable binding site for [3H]LRRK2-IN-1 in rat kidney, rat brain striatum and human brain striatum with K d of 26 +/- 3 and 43 +/- 8, 48 +/- 2 nM, respectively. In rat, the density of LRRK2 binding sites (B max) was higher in kidney (6.4 +/- 0.04 pmol/mg) than in brain (2.5 +/- 0.03 pmol/mg), however, in human brain striatum, the B max was 0.73 +/- 0.01 pmol/mg protein. Autoradiography imaging in striatum of rat and human brain tissues gave results consistent with binding studies. In in vivo biodistribution and blocking studies in mice, co-administration with Pf-06447475 (10 mg/kg) reduced the uptake of [3H]LRRK2-IN-1 (%ID/g) by 50-60% in the kidney or brain. CONCLUSION: The high LRRK2 brain density observed in our study suggests the feasibility for positron emission tomography imaging of LRRK2 (a potential target) with radioligands of higher affinity and specificity.

The brain noradrenaline (NA) system, particularly NA transporters (NAT), are thought to play an important role in modulating impulsive behavior. Impaired impulsivity is implicated in a variety of neuropsychiatric conditions; however, an in vivo link between central NAT availability and human impulsivity has not been shown. Using positron emission tomography (PET) and S,S-[11C]O-methylreboxetine (MRB), we tested whether NAT availability is associated with this basic behavioral trait based on the Barratt Impulsiveness Scale (BIS-11) in twenty healthy individuals (12 females, 33.8+/-9.3, 21-52 years of age) with a body mass index (BMI) ranging from 21.7kg/m2 to 47.8kg/m2. Applying both voxel-wise and volume-of-interest (VOI) based analyses, we found that distribution volume ratios (DVR) used as PET outcome measures negatively correlated with BIS-11 total scores in the orbitofrontal cortex (OFC) and in the hippocampus as well as in parts of the cerebellar cortex. These associations however did not remain after correction for multiple testing. Thus, although it appears that low NAT availability is associated with greater scores of impaired behavioral control, this needs to be confirmed in a larger series of individuals with highly impulsive behavior.

PURPOSE: The brain noradrenaline (NA) system plays an important role in the central nervous control of energy balance and is thus implicated in the pathogenesis of obesity. The specific processes modulated by this neurotransmitter which lead to obesity and overeating are still a matter of debate. METHODS: We tested the hypothesis that in vivo NA transporter (NAT) availability is changed in obesity by using positron emission tomography (PET) and S,S-[11C]O-methylreboxetine (MRB) in twenty subjects comprising ten highly obese (body mass index BMI > 35 kg/m2), metabolically healthy, non-depressed individuals and ten non-obese (BMI < 30 kg/m2) healthy controls. RESULTS: Overall, we found no significant differences in binding potential (BPND) values between obese and non-obese individuals in the investigated brain regions, including the NAT-rich thalamus (0.40 +/- 0.14 vs. 0.41 +/- 0.18; p = 0.84) though additional discriminant analysis correctly identified individual group affiliation based on regional BPND in all but one (control) case. Furthermore, inter-regional correlation analyses indicated different BPND patterns between both groups but this did not survive testing for multiple comparions. CONCLUSIONS: Our data do not find an overall involvement of NAT changes in human obesity. However, preliminary secondary findings of distinct regional and associative patterns warrant further investigation.