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Individual differences in dopamine D receptor availability correlate with reward valuation.
Dang LC, Samanez-Larkin GR, Castrellon JJ, Perkins SF, Cowan RL, Zald DH
(2018) Cogn Affect Behav Neurosci 18: 739-747
MeSH Terms: Adult, Anticipation, Psychological, Benzamides, Brain, Brain Mapping, Cerebrovascular Circulation, Female, Fluorine Radioisotopes, Humans, Individuality, Magnetic Resonance Imaging, Male, Oxygen, Positron-Emission Tomography, Radiopharmaceuticals, Receptors, Dopamine D2, Reward
Show Abstract · Added April 15, 2019
Reward valuation, which underlies all value-based decision-making, has been associated with dopamine function in many studies of nonhuman animals, but there is relatively less direct evidence for an association in humans. Here, we measured dopamine D receptor (DRD2) availability in vivo in humans to examine relations between individual differences in dopamine receptor availability and neural activity associated with a measure of reward valuation, expected value (i.e., the product of reward magnitude and the probability of obtaining the reward). Fourteen healthy adult subjects underwent PET with [F]fallypride, a radiotracer with strong affinity for DRD2, and fMRI (on a separate day) while performing a reward valuation task. [F]fallypride binding potential, reflecting DRD2 availability, in the midbrain correlated positively with neural activity associated with expected value, specifically in the left ventral striatum/caudate. The present results provide in vivo evidence from humans showing midbrain dopamine characteristics are associated with reward valuation.
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17 MeSH Terms
Evaluation of the novel TSPO radiotracer 2-(7-butyl-2-(4-(2-([F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide in a preclinical model of neuroinflammation.
Tang D, Fujinaga M, Hatori A, Zhang Y, Yamasaki T, Xie L, Mori W, Kumata K, Liu J, Manning HC, Huang G, Zhang MR
(2018) Eur J Med Chem 150: 1-8
MeSH Terms: Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Fluorine Radioisotopes, Humans, Inflammation, Ischemia, Male, Mice, Molecular Probes, Molecular Structure, Positron-Emission Tomography, Pyrazoles, Pyrimidines, Radioactive Tracers, Radiopharmaceuticals, Rats, Rats, Sprague-Dawley, Receptors, GABA, Structure-Activity Relationship, Tissue Distribution
Show Abstract · Added March 22, 2018
Translocator Protein (18 kDa, TSPO) is regarded as a useful biomarker for neuroinflammation imaging. TSPO PET imaging could be used to understand the role of neuroinflammation in brain diseases and as a tool for evaluating novel therapeutic effects. As a promising TSPO probe, [F]DPA-714 is highly specific and offers reliable quantification of TSPO in vivo. In this study, we further radiosynthesized and evaluated another novel TSPO probe, 2-(7-butyl-2-(4-(2-[F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([F]VUIIS1018A), which features a 700-fold higher binding affinity for TSPO than that of [F]DPA-714. We evaluated the performance of [F]VUIIS1018A using dynamic in vivo PET imaging, radiometabolite analysis, in vitro autoradiography assays, biodistribution analysis, and blocking assays. In vivo study using this probe demonstrated high signal-to-noise ratio, binding potential (BP), and binding specificity in preclinical neuroinflammation studies. Taken together, these findings indicate that [F]VUIIS1018A may serve as a novel TSPO PET probe for neuroinflammation imaging.
Copyright © 2018. Published by Elsevier Masson SAS.
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21 MeSH Terms
FTO affects food cravings and interacts with age to influence age-related decline in food cravings.
Dang LC, Samanez-Larkin GR, Smith CT, Castrellon JJ, Perkins SF, Cowan RL, Claassen DO, Zald DH
(2018) Physiol Behav 192: 188-193
MeSH Terms: Adult, Aged, Aged, 80 and over, Aging, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Benzamides, Body Mass Index, Brain, Craving, Feeding Behavior, Female, Food, Genetic Association Studies, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Positron-Emission Tomography, Pyrrolidines, Radiopharmaceuticals, Receptors, Dopamine D2, Young Adult
Show Abstract · Added March 21, 2018
The fat mass and obesity associated gene (FTO) was the first gene identified by genome-wide association studies to correlate with higher body mass index (BMI) and increased odds of obesity. FTO remains the locus with the largest and most replicated effect on body weight, but the mechanism whereby FTO affects body weight and the development of obesity is not fully understood. Here we tested whether FTO is associated with differences in food cravings and a key aspect of dopamine function that has been hypothesized to influence food reward mechanisms. Moreover, as food cravings and dopamine function are known to decline with age, we explored effects of age on relations between FTO and food cravings and dopamine function. Seven-eight healthy subjects between 22 and 83years old completed the Food Cravings Questionnaire and underwent genotyping for FTO rs9939609, the first FTO single nucleotide polymorphism associated with obesity. Compared to TT homozygotes, individuals carrying the obesity-susceptible A allele had higher total food cravings, which correlated with higher BMI. Additionally, food cravings declined with age, but this age effect differed across variants of FTO rs9939609: while TT homozygotes showed the typical age-related decline in food cravings, there was no such decline among A carriers. All subjects were scanned with [18F]fallypride PET to assess a recent proposal that at the neurochemical level FTO alters dopamine D2-like receptor (DRD2) function to influence food reward related mechanisms. However, we observed no evidence of FTO effects on DRD2 availability.
Copyright © 2017 Elsevier Inc. All rights reserved.
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22 MeSH Terms
In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction.
Barry RL, Byun NE, Tantawy MN, Mackey CA, Wilson GH, Stark AJ, Flom MP, Gee LC, Quarles CC
(2018) Brain Imaging Behav 12: 87-95
MeSH Terms: Animals, Antineoplastic Agents, Brain, Brain Mapping, Cognitive Dysfunction, Conditioning (Psychology), Disease Models, Animal, Doxorubicin, Fear, Female, Fluorodeoxyglucose F18, Magnetic Resonance Imaging, Neuroimaging, Positron-Emission Tomography, Radiopharmaceuticals, Rats, Sprague-Dawley, Recognition (Psychology), Tomography, X-Ray Computed
Show Abstract · Added March 14, 2018
Adjuvant chemotherapy has been used for decades to treat cancer, and it is well known that disruptions in cognitive function and memory are common chemotherapeutic adverse effects. However, studies using neuropsychological metrics have also reported group differences in cognitive function and memory before or without chemotherapy, suggesting that complex factors obscure the true etiology of chemotherapy-induced cognitive dysfunction (CICD) in humans. Therefore, to better understand possible mechanisms of CICD, we explored the effects of CICD in rats through cognition testing using novel object recognition (NOR) and contextual fear conditioning (CFC), and through metabolic neuroimaging via [F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Cancer-naïve, female Sprague-Dawley rats were administered either saline (1 mL/kg) or doxorubicin (DOX) (1 mg/kg in a volume of 1 mL/kg) weekly for five weeks (total dose = 5 mg/kg), and underwent cognition testing and PET imaging immediately following the treatment regime and 30 days post treatment. We did not observe significant differences with CFC testing post-treatment for either group. However, the chemotherapy group exhibited significantly decreased performance in the NOR test and decreased F-FDG uptake only in the prefrontal cortex 30 days post-treatment. These results suggest that long-term impairment within the prefrontal cortex is a plausible mechanism of CICD in this study, suggesting DOX-induced toxicity in the prefrontal cortex at the dose used.
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18 MeSH Terms
Reduced effects of age on dopamine D2 receptor levels in physically active adults.
Dang LC, Castrellon JJ, Perkins SF, Le NT, Cowan RL, Zald DH, Samanez-Larkin GR
(2017) Neuroimage 148: 123-129
MeSH Terms: Adult, Aged, Aged, 80 and over, Aging, Benzamides, Brain, Cross-Sectional Studies, Exercise, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Positron-Emission Tomography, Radiopharmaceuticals, Receptors, Dopamine D2, Receptors, Dopamine D3, Young Adult
Show Abstract · Added April 6, 2017
Physical activity has been shown to ameliorate dopaminergic degeneration in non-human animal models. However, the effects of regular physical activity on normal age-related changes in dopamine function in humans are unknown. Here we present cross-sectional data from forty-four healthy human subjects between 23 and 80 years old, showing that typical age-related dopamine D2 receptor loss, assessed with PET [18F]fallypride, was significantly reduced in physically active adults compared to less active adults.
Copyright © 2017 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Utility of [F]FSPG PET to Image Hepatocellular Carcinoma: First Clinical Evaluation in a US Population.
Kavanaugh G, Williams J, Morris AS, Nickels ML, Walker R, Koglin N, Stephens AW, Washington MK, Geevarghese SK, Liu Q, Ayers D, Shyr Y, Manning HC
(2016) Mol Imaging Biol 18: 924-934
MeSH Terms: Acetates, Adult, Aged, Amino Acid Transport System y+, Carbon Radioisotopes, Carcinoma, Hepatocellular, Female, Glutamates, Glutamic Acid, Humans, Liver Neoplasms, Male, Middle Aged, Positron-Emission Tomography, Radiopharmaceuticals, Sequence Analysis, RNA, Tissue Array Analysis
Show Abstract · Added April 6, 2017
PURPOSE - Non-invasive imaging is central to hepatocellular carcinoma (HCC) diagnosis; however, conventional modalities are limited by smaller tumors and other chronic diseases that are often present in patients with HCC, such as cirrhosis. This pilot study evaluated the feasibility of (4S)-4-(3-[F]fluoropropyl)-L-glutamic acid ([F]FSPG) positron emission tomography (PET)/X-ray computed tomography (CT) to image HCC. [F]FSPG PET/CT was compared to standard-of-care (SOC) magnetic resonance imaging (MRI) and CT, and [C]acetate PET/CT, commonly used in this setting. We report the largest cohort of HCC patients imaged to date with [F]FSPG PET/CT and present the first comparison to [C]acetate PET/CT and SOC imaging. This study represents the first in a US HCC population, which is distinguished by different underlying comorbidities than non-US populations.
PROCEDURES - x transporter RNA and protein levels were evaluated in HCC and matched liver samples from The Cancer Genome Atlas (n = 16) and a tissue microarray (n = 83). Eleven HCC patients who underwent prior MRI or CT scans were imaged by [F]FSPG PET/CT, with seven patients also imaged with [C]acetate PET/CT.
RESULTS - x transporter RNA and protein levels were elevated in HCC samples compared to background liver. Over 50 % of low-grade HCCs and ~70 % of high-grade tumors exceeded background liver protein expression. [F]FSPG PET/CT demonstrated a detection rate of 75 %. [F]FSPG PET/CT also identified an HCC devoid of typical MRI enhancement pattern. Patients scanned with [F]FSPG and [C]acetate PET/CT exhibited a 90 and 70 % detection rate, respectively. In dually positive tumors, [F]FSPG accumulation consistently resulted in significantly greater tumor-to-liver background ratios compared with [C]acetate PET/CT.
CONCLUSIONS - [F]FSPG PET/CT is a promising modality for HCC imaging, and larger studies are warranted to examine [F]FSPG PET/CT impact on diagnosis and management of HCC. [F]FSPG PET/CT may also be useful for phenotyping HCC tumor metabolism as part of precision cancer medicine.
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17 MeSH Terms
Associations between dopamine D2 receptor availability and BMI depend on age.
Dang LC, Samanez-Larkin GR, Castrellon JJ, Perkins SF, Cowan RL, Zald DH
(2016) Neuroimage 138: 176-183
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Aging, Benzamides, Biological Availability, Body Mass Index, Brain, Female, Humans, Male, Middle Aged, Molecular Imaging, Positron-Emission Tomography, Pyrrolidines, Radiopharmaceuticals, Receptors, Dopamine D2, Receptors, Dopamine D3, Reproducibility of Results, Sensitivity and Specificity, Statistics as Topic, Tissue Distribution, Young Adult
Show Abstract · Added April 6, 2017
OBJECTIVE - The dopamine D2/3 receptor subtypes (DRD2/3) are the most widely studied neurotransmitter biomarker in research on obesity, but results to date have been inconsistent, have typically involved small samples, and have rarely accounted for subjects' ages despite the large impact of age on DRD2/3 levels. We aimed to clarify the relation between DRD2/3 availability and BMI by examining this association in a large sample of subjects with BMI spanning the continuum from underweight to extremely obese.
SUBJECTS - 130 healthy subjects between 18 and 81years old underwent PET with [18F]fallypride, a high affinity DRD2/3 ligand.
RESULTS - As expected, DRD2/3 availability declined with age. Critically, age significantly interacted with DRD2/3 availability in predicting BMI in the midbrain and striatal regions (caudate, putamen, and ventral striatum). Among subjects under 30years old, BMI was not associated with DRD2/3 availability. By contrast, among subjects over 30years old, BMI was positively associated with DRD2/3 availability in the midbrain, putamen, and ventral striatum.
CONCLUSION - The present results are incompatible with the prominent dopaminergic hypofunction hypothesis that proposes that a reduction in DRD2/3 availability is associated with increased BMI, and highlights the importance of age in assessing correlates of DRD2/3 function.
Copyright © 2016 Elsevier Inc. All rights reserved.
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24 MeSH Terms
Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.
Gifford A, Towse TF, Walker RC, Avison MJ, Welch EB
(2016) Am J Physiol Endocrinol Metab 311: E95-E104
MeSH Terms: Adipose Tissue, Brown, Adult, Cold Temperature, Female, Fluorodeoxyglucose F18, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Positron Emission Tomography Computed Tomography, Radiopharmaceuticals, Thermogenesis, Thoracic Wall, Young Adult
Show Abstract · Added May 24, 2016
Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.
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14 MeSH Terms
Modulation of impulsivity and reward sensitivity in intertemporal choice by striatal and midbrain dopamine synthesis in healthy adults.
Smith CT, Wallace DL, Dang LC, Aarts E, Jagust WJ, D'Esposito M, Boettiger CA
(2016) J Neurophysiol 115: 1146-56
MeSH Terms: Adult, Choice Behavior, Dopamine, Female, Humans, Impulsive Behavior, Male, Mesencephalon, Positron-Emission Tomography, Putamen, Radiopharmaceuticals, Reaction Time, Reward, Tyrosine
Show Abstract · Added February 9, 2017
Converging evidence links individual differences in mesolimbic and mesocortical dopamine (DA) to variation in the tendency to choose immediate rewards ("Now") over larger, delayed rewards ("Later"), or "Now bias." However, to date, no study of healthy young adults has evaluated the relationship between Now bias and DA with positron emission tomography (PET). Sixteen healthy adults (ages 24-34 yr; 50% women) completed a delay-discounting task that quantified aspects of intertemporal reward choice, including Now bias and reward magnitude sensitivity. Participants also underwent PET scanning with 6-[(18)F]fluoro-l-m-tyrosine (FMT), a radiotracer that measures DA synthesis capacity. Lower putamen FMT signal predicted elevated Now bias, a more rapidly declining discount rate with increasing delay time, and reduced willingness to accept low-interest-rate delayed rewards. In contrast, lower FMT signal in the midbrain predicted greater sensitivity to increasing magnitude of the Later reward. These data demonstrate that intertemporal reward choice in healthy humans varies with region-specific measures of DA processing, with regionally distinct associations with sensitivity to delay and to reward magnitude.
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14 MeSH Terms
Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study.
Buck JR, McKinley ET, Fu A, Abel TW, Thompson RC, Chambless L, Watchmaker JM, Harty JP, Cooper MK, Manning HC
(2015) PLoS One 10: e0141659
MeSH Terms: Acetanilides, Animals, Brain Neoplasms, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Glioma, Humans, Male, Mice, Neoplasm Transplantation, Positron-Emission Tomography, Radiopharmaceuticals, Rats, Receptors, GABA, Sensitivity and Specificity, Tissue Array Analysis
Show Abstract · Added February 11, 2016
Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes.
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16 MeSH Terms