Faculty Bibliography

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.

OBJECTIVES: Noradrenergic dysfunction is implicated in obesity. The norepinephrine transporter (NET) regulates the synaptic availability of norepinephrine. However, NET availability has not been previously characterized in vivo in obese people using Positron Emission Tomography (PET) imaging. Here we report findings evaluating NET availability in individuals with obesity and matched lean (i.e., normal weight) comparison subjects. METHODS: Seventeen obese but otherwise healthy individuals with a mean+/-SD body mass index (BMI) of 34.7+/-2.6 and 17 lean individuals with a mean+/-SD BMI of 23.1+/-1.4 were studied using a high-resolution research tomograph (HRRT) and (S,S)-[11C]O-methylreboxetine ([11C]-MRB), a radioligand selective for the NET. The regional brain NET binding potential (BPND) was estimated by the multilinear reference tissue model 2 (MRTM2) with the occipital cortex as a reference region. BPND for regions of interest were obtained with the Automated Anatomic Labeling (AAL) template registered to individual's structural MR scans. RESULTS: Obese individuals had lower NET BPND values in the thalamus (p<0.038, 27% reduction) including within the pulvinar (p<0.083, 30% reduction), but not in the hypothalamus, locus coeruleus or the raphe nuclei, compared to lean individuals. When age was included as a covariate, the difference in NET BPND values remained significant in the thalamus (p<0.025) and pulvinar (p<0.042). CONCLUSIONS: These results indicate that NET availability is decreased in the thalamus, including the pulvinar, in obese individuals. These findings further support data indicating noradrenergic dysfunction in obesity and suggest impaired NE clearance in obesity.

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

beta-Amyloid (A beta) plaques in the blood vessels of the brain are associated with cerebral amyloid angiopathy (CAA), which is a common cause of stroke and vascular diseases. Imaging agents that can differentiate between A beta plaques in the brain and those on the walls of cerebrovascular vessels will provide non-invasive biomarkers to interrogate the pathogenesis of CAA and give insights into the mechanisms, significance and impact of A beta-CAA for developing effective therapies for CAA and stroke. A new series of Tc-99m-labeled benzothiazole and stilbene derivatives with positive charge were developed and evaluated for selectively targeting A beta plaques in the blood vessels of the brain. The rhenium complexes 6, 7, 13 and 14 displayed medium binding affinity to A beta(1-42) aggregates with K-i values of 162, 37, 366 and 78 nM, respectively. In vitro fluorescence staining of 7 and 14 demonstrated an intense labeling of A beta plaques associated with blood vessel walls on brain sections of a patient with Alzheimer's diseases. A relatively low initial brain uptake for [Tc-99m]7 and [Tc-99m]14, 0.18 and 0.24 ID% per gram, respectively, suggests that they may be useful SPECT imaging agents for selectively detecting A beta plaques associated with cerebral vessels in the living human brain. C1 [Jia, Jianhua; Cui, Mengchao; Wang, Xuedan; Jia, Hongmei; Liu, Boli] Beijing Normal Univ, Coll Chem, Minist Educ, Key Lab Radiopharmaceut, Beijing 100875, Peoples R China. [Dai, Jiapei] South Cent Univ Nationalities, Wuhan Inst Neurosci & Neuroengn, Wuhan, Peoples R China. [Ding, Yu-Shin] NYU, Sch Med, Dept Chem, Dept Radiol, New York, NY USA. [Ding, Yu-Shin] NYU, Sch Med, Dept Psychiat, Dept Chem, New York, NY USA