Faculty Bibliography

INTRODUCTION: Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with (11)C-MRB ((S,S)-(11)C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. METHODS: Ten healthy, Caucasian subjects (5 M: age 24.6+/-2.6, BMI 21.6+/-2.7kg/m(2); 5 F: age 25.4+/-2.1, BMI 22.1+/-1.0kg/m(2)) underwent (11)C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15 degrees C) compared to (18)F-FDG PET-CT imaging. Uptake of (11)C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. RESULTS: As expected, (18)F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT (11)C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0+/-0.3 vs. cold 1.1+/-0.3, p=0.31; BAT/muscle DVR: RT 2.3+/-0.7 vs. cold 2.5+/-0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of (11)C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with (18)F-FDG (p=0.63). Furthermore, there were gender differences in (11)C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in (11)C-MRB as a function of both body composition and body temperature. CONCLUSIONS: Unlike (18)F-FDG, the uptake of (11)C-MRB in BAT offers a unique opportunity to investigate the role of BAT in humans under basal, room temperature conditions.

PURPOSE: Dynamic FDG imaging for prostate cancer characterization is limited by generally small size and low uptake in prostate tumors. Our aim in this pilot study was to explore feasibility of simultaneous PET/MRI to guide localization of prostate lesions for dynamic FDG analysis using a graphical approach. METHODS: Three patients with biopsy-proven prostate cancer underwent simultaneous FDG PET/MRI, incorporating dynamic prostate imaging. Histology and multiparametric MRI findings were used to localize tumors, which in turn guided identification of tumors on FDG images. Regions of interest were manually placed on tumor and benign prostate tissue. Blood activity was extracted from a region of interest placed on the femoral artery on PET images. FDG data were analyzed by graphical analysis using the influx constant Ki (Patlak analysis) when FDG binding seemed irreversible and distribution volume VT (reversible graphical analysis) when FDG binding seemed reversible given the presence of washout. RESULTS: Given inherent coregistration, simultaneous acquisition facilitated use of MRI data to localize small lesions on PET and subsequent graphical analysis in all cases. In 2 cases with irreversible binding, tumor had higher Ki than benign using Patlak analysis (0.023 vs 0.006 and 0.019 vs 0.008 mL/cm per minute). In 1 case appearing reversible, tumor had higher VT than benign using reversible graphical analysis (0.68 vs 0.52 mL/cm). CONCLUSIONS: Simultaneous PET/MRI allows localization of small prostate tumors for dynamic PET analysis. By taking advantage of inclusion of the femoral arteries in the FOV, we applied advanced PET data analysis methods beyond conventional static measures and without blood sampling.

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: Evidence from animal models and postmortem human studies points to the importance of the dopamine D3 receptor (D3R) in cocaine dependence (CD). The objective of this pilot study was to use the D3R-preferring radioligand [(11)C](+)PHNO to compare receptor availability in groups with and without CD. METHODS: Ten medically healthy, non-treatment seeking CD subjects (mean age 41+/-8) in early abstinence were compared to 10 healthy control (HC) subjects (mean age 41+/-6) with no history of cocaine or illicit substance abuse. Binding potential (BPND), a measure of available receptors, was determined with parametric images, computed using the simplified reference tissue model (SRTM2) with the cerebellum as the reference region. RESULTS: BPND in CD subjects was higher in D3R-rich areas including the substantia nigra ((SN) 29%; P=0.03), hypothalamus (28%; P=0.02) and amygdala (35%; P=0.03). No between-group differences were observed in the striatum or pallidum. BPND values in the SN (r=+0.83; P=0.008) and pallidum (r=+0.67; P=0.03) correlated with years of cocaine use. CONCLUSIONS: Between-group differences suggest an important role for dopaminergic transmission in the SN, hypothalamus and amygdala in CD. Such findings also highlight the potential relevance of D3R as a medication development target in CD.

11C-(+)-4-propyl-9-hydroxynaphthoxazine (11C-(+)-PHNO) is an agonist radioligand for imaging dopamine D2 and D3 receptors in the human brain with PET. In this study we evaluated the reproducibility of 11C-(+)-PHNO binding parameters using a within-day design and assessed parametric imaging methods. METHODS: Repeated studies were performed in 8 subjects, with simultaneous measurement of the arterial input function and plasma free fraction. Two 11C-(+)-PHNO scans for the same subject were separated by 5.4 +/- 0.7 h. After compartment models were evaluated, 11C-(+)-PHNO volumes of distribution (VT) and binding potentials relative to the concentration of tracer in plasma (BPP), nondisplaceable tracer in tissue (BPND), and free tracer in tissue (BPF) were quantified using the multilinear analysis MA1 method, with the cerebellum as the reference region. Parametric images of BPND were also computed using the simplified reference tissue model (SRTM) and SRTM2. RESULTS: The test-retest variability of 11C-(+)-PHNO BPND was 9% in D2-rich regions (caudate and putamen). Among D3-rich regions, variability was low in the pallidum (6%) but higher in substantia nigra (19%), thalamus (14%), and hypothalamus (21%). No significant mass carry-over effect was observed in D3-rich regions, although a trend in BPND was present in the substantia nigra (-14% +/- 15%). Because of the relatively fast kinetics, low-noise BPND parametric images were obtained with both SRTM and SRTM2 without spatial smoothing. CONCLUSION: 11C-(+)-PHNO can be used to compute low-noise parametric images in both D2- and D3-rich regions in humans.