Publications by authors named "Yu-Shin Ding"

90 Publications

Cardiac sympathetic innervation and vesicular storage in pure autonomic failure.

Ann Clin Transl Neurol 2020 10 10;7(10):1908-1918. Epub 2020 Sep 10.

Department of Internal Medicine, Chaim Sheba Medical Center, Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel.

Objective: Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), absence of signs of central neurodegeneration, and profound deficiency of the sympathetic neurotransmitter norepinephrine. Reports have disagreed about mechanisms of the noradrenergic lesion. Neuropathological studies have highlighted denervation, while functional studies have emphasized deficient vesicular sequestration of cytoplasmic catecholamines in extant neurons. We examined both aspects by a combined positron emission tomographic (PET) neuroimaging approach using C-methylreboxetine ( C-MRB), a selective ligand for the cell membrane norepinephrine transporter, to quantify interventricular septal myocardial noradrenergic innervation and using F-dopamine ( F-DA) to assess intraneuronal vesicular storage in the same subjects.

Methods: Seven comprehensively tested PAF patients and 11 controls underwent C-MRB PET scanning for 45 minutes (dynamic 5X1', 3X5', 1X10', static 15 minutes) and F-DA scanning for 30 minutes (same dynamic imaging sequence) after 3-minute infusions of the tracers on separate days.

Results: In the PAF group septal C-MRB-derived radioactivity in the static frame was decreased by 26.7% from control (p = 0.012). After adjustment for nonspecific binding of C-MRB, the PAF group had a 41.1% mean decrease in myocardial C-MRB-derived radioactivity (p = 0.015). The PAF patients had five times faster postinfusion loss of F-DA-derived radioactivity (70 ± 3% vs. 14 ± 8% by 30 minutes, p < 0.0001). At all time points after infusion of F-DA and C-MRB mean F/ C ratios in septal myocardium were lower in the PAF than control group.

Interpretation: PAF entails moderately decreased cardiac sympathetic innervation and a substantial vesicular storage defect in residual nerves.
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http://dx.doi.org/10.1002/acn3.51184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545586PMC
October 2020

PET imaging study of brown adipose tissue (BAT) activity in mice devoid of receptor for advanced glycation end products (RAGE).

J Biosci 2019 Sep;44(4)

Department of Radiology, New York University School of Medicine, New York, USA.

Brown adipose tissue (BAT) is responsible for adaptive thermogenesis. We previously showed that genetic deficiency of receptor for advanced glycation end products (RAGE) prevented the effects of high-fat diet (HFD). This study was to compare BAT activity in RAGE knock out (Ager, RKO) and wild-type (WT) mice after treated with HFD or LFD. [F]FDG PET-CT imaging under identical cold-stimulated conditions and mean standard uptake values (SUV), ratio of SUV/SUV (SUVR, muscle as the reference region) and percentage ID/g were used for BAT quantification. The results showed that [F]FDG uptake (e.g., SUVR) in WT-HFD mice was significantly reduced (three-fold) as compared to that in WT-LFD (1.40 +/- 0.07 and 4.03 +/- 0.38; P = 0.004). In contrast, BAT activity in RKO mice was not significantly affected by HFD, with SUVR: 2.14 +/- 0.10 and SUVR: 1.52 +/- 0.13 (P = 0.3). The uptake in WT-LFD was almost double of that in RKO-LFD (P = 0.004); however, there was no significant difference between RKO-HFD and WT-HFD mice (P = 0.3). These results, corroborating our previous findings on the measurement of mRNA transcripts for UCP1 in the BAT, suggest that RAGE may contribute to altered energy expenditure and provide a protective effect against HFD by Ager deletion (Ager ).
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September 2019

Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls.

Stress 2019 01 29;22(1):93-102. Epub 2018 Oct 29.

a Integrated Research and Treatment Center (IFB) Adiposity Diseases , Leipzig University Medical Center , Leipzig , Germany.

The central noradrenaline (NA) stress-response network co-mediates hypothalamic-pituitary-adrenal (HPA) axis activation and arginine-vasopressin (AVP) release. Dysregulation of these systems contributes to stress-related diseases such as human obesity, but their interrelation remains unclear. The study was aimed to test for the first time in vivo whether central noradrenergic activity quantitatively indexed by the availability of the presynaptic NA transporter (NAT) is associated with HPA axis responsiveness as measured with the combined dexamethasone suppression/corticotropin releasing hormone stimulation (dex/CRH) test and copeptin as a surrogate marker of the serum AVP tone in highly obese, otherwise, healthy individuals compared to age- and sex-matched non-obese, healthy controls. In order to assess central NAT availability, positron emission tomography (PET) was applied using the NAT-selective radiotracer S,S-[C]O-methylreboxetine (MRB) and correlated with curve indicators derived from the dex/CRH test (maximum, MAX, and area under the curve, AUC, for cortisol and adrenocorticotropic hormone, ACTH) as well as with copeptin. In non-obese controls, positive correlations were found between the NAT distribution volume ratios (DVR) of the orbitofrontal cortex (OFC) and the amygdala with the HPA response (OFC: ACTH r = 0.87, p = .001; cortisol r = 0.86, p = .002; amygdala: ACTH r = 0.86, p = .002; cortisol r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisol, r = -0.66, p = .04) and with copeptin (r = -0.71, p = .02). This association of central NAT availability with HPA axis responsiveness and copeptin suggests a mechanistic interaction between noradrenergic transmission with HPA axis activity and the serum AVP system that differs between non-obese individuals with prefrontal-limbic involvement and obesity with a hypothalamic-centered relationship. Whether the latter finding contributes to obesogenic behavior needs to be further explored.
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http://dx.doi.org/10.1080/10253890.2018.1511698DOI Listing
January 2019

Noradrenaline transporter availability on [C]MRB PET predicts weight loss success in highly obese adults.

Eur J Nucl Med Mol Imaging 2018 07 7;45(9):1618-1625. Epub 2018 Apr 7.

Integrated Research and Treatment Center (IFB) AdiposityDiseases, University Medical Center, Leipzig, Germany.

Purpose: 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: We aimed to compare central NA transporter (NAT) availability in ten obese, otherwise healthy individuals with a body mass index (BMI) of 42.4 ± 3.7 kg/m (age 34 ± 9 years, four women) and ten matched non-obese, healthy controls (BMI 23.9 ± 2.5 kg/m, age 33 ± 10 years, four women) who underwent PET with the NAT-selective radiotracer (S,S)-[C]O-methylreboxetine (MRB) before and 6 months after dietary intervention.

Results: MRI-based individual volume-of-interest analyses revealed an increase in binding potential (BP) in the insula and the hippocampus of obese individuals, which correlated well with changes in BMI (-3.3 ± 5.3%; p = 0.03) following completion of the dietary intervention. Furthermore, voxel-wise regression analyses showed that lower BP in these regions, but also in the midbrain and the prefrontal cortex, at baseline was associated with higher achieved weight loss (e.g., hippocampal area R = 0.80; p < 0.0001). No changes were observed in non-obese controls.

Conclusion: 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.
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http://dx.doi.org/10.1007/s00259-018-4002-7DOI Listing
July 2018

Noradrenergic Activity in the Human Brain: A Mechanism Supporting the Defense Against Hypoglycemia.

J Clin Endocrinol Metab 2018 06;103(6):2244-2252

Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut.

Context: Hypoglycemia, one of the major factors limiting optimal glycemic control in insulin-treated patients with diabetes, elicits a brain response to restore normoglycemia by activating counterregulation. Animal data indicate that local release of norepinephrine (NE) in the hypothalamus is important for triggering hypoglycemia-induced counterregulatory (CR) hormonal responses.

Objective: To examine the potential role of brain noradrenergic (NA) activation in humans during hypoglycemia.

Design: A hyperinsulinemic-hypoglycemic clamp was performed in conjunction with positron emission tomographic imaging.

Participants: Nine lean healthy volunteers were studied during the hyperinsulinemic-hypoglycemic clamp.

Design: Participants received intravenous injections of (S,S)-[11C]O-methylreboxetine ([11C]MRB), a highly selective NE transporter (NET) ligand, at baseline and during hypoglycemia.

Results: 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: Insulin-induced hypoglycemia initiated a complex brain NA response in humans. Raphe nuclei, a region involved in regulating autonomic output, motor activity, and hunger, had increased NA activity, whereas the hypothalamus showed a NET-binding pattern that was associated with the individual's CR response magnitude. These findings suggest that NA output most likely is important for modulating brain responses to hypoglycemia in humans.
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http://dx.doi.org/10.1210/jc.2017-02717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456998PMC
June 2018

A Positron Emission Tomography Study of Norepinephrine Transporter Occupancy and Its Correlation with Symptom Response in Depressed Patients Treated with Quetiapine XR.

Int J Neuropsychopharmacol 2018 02;21(2):108-113

Center for Health Evaluation and Outcome Sciences, University of British Columbia, Vancouver, Canada.

Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy.

Methods: In this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7.

Results: Norepinephrine transporter 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 norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter 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% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L.

Conclusion: These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.
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http://dx.doi.org/10.1093/ijnp/pyx066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793822PMC
February 2018

The association between in vivo central noradrenaline transporter availability and trait impulsivity.

Psychiatry Res Neuroimaging 2017 Sep 23;267:9-14. Epub 2017 Jun 23.

Integrated Treatment and Research Centre (IFB) AdiposityDiseases, Leipzig University Medical Centre, Liebigstraße 20, 04103 Leipzig, Germany; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.

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-[C]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/m to 47.8kg/m. 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.
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http://dx.doi.org/10.1016/j.pscychresns.2017.06.013DOI Listing
September 2017

Erratum to: Synthesis and In Vitro and In Vivo Evaluation of [H]LRRK2-IN-1 as a Novel Radioligand for LRRK2.

Mol Imaging Biol 2017 12;19(6):846

Department of Radiology, New York University School of Medicine, New York, NY, USA.

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http://dx.doi.org/10.1007/s11307-017-1086-6DOI Listing
December 2017

Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies.

Lancet Neurol 2017 05 20;16(5):351-359. Epub 2017 Mar 20.

University of British Columbia, Department of Medicine, Vancouver, BC, Canada; Pacific Parkinson's Research Centre, Vancouver, BC, Canada.

Background: People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes.

Methods: We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (F-6-fluoro-L-dopa; F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age.

Findings: Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p<0·0001), striatum (compared with people with sporadic Parkinson's disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease.

Interpretation: Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa.

Funding: Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada.
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http://dx.doi.org/10.1016/S1474-4422(17)30056-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477770PMC
May 2017

Synthesis and In Vitro and In Vivo Evaluation of [H]LRRK2-IN-1 as a Novel Radioligand for LRRK2.

Mol Imaging Biol 2017 12;19(6):837-845

Department of Radiology, New York University School of Medicine, New York, USA.

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 (IC, K , B , autoradiography) and in vivo (biodistribution, and blocking experiments) evaluations in rodents and human striatum tissues.

Procedures: [H]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 IC, K , and B 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 [H]LRRK2-IN-1 in rat kidney, rat brain striatum and human brain striatum with K of 26 ± 3 and 43 ± 8, 48 ± 2 nM, respectively. In rat, the density of LRRK2 binding sites (B ) 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 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 [H]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.
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http://dx.doi.org/10.1007/s11307-017-1070-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597475PMC
December 2017

On the potential for RF heating in MRI to affect metabolic rates and FDG signal in PET/MR: simulations of long-duration, maximum normal mode heating.

Med Phys 2017 Feb 30;44(2):589-596. Epub 2017 Jan 30.

Department of Radiology, New York University, New York, NY, 10016, USA.

Purpose: To examine the possibility that MR-induced RF power deposition (SAR) and the resulting effects on temperature-dependent metabolic rates or perfusion rates might affect observed 18FDG signal in PET/MR.

Methods: Using numerical simulations of the SAR, consequent temperature increase, effect on rates of metabolism or perfusion, and [18FDG] throughout the body, we simulated the potential effect of maximum-allowable whole-body SAR for the entire duration of an hour-long PET/MR scan on observed PET signal for two different 18FDG injection times: one hour before onset of imaging and concurrent with the beginning of imaging. This was all repeated three times with the head, the heart, and the abdomen (kidneys) at the center of the RF coil.

Results: Qualitatively, little effect of MR-induced heating is observed on simulated PET images. Maximum relative increases in PET signal (26% and 31% increase, respectively, for the uptake models based on metabolism and the perfusion) occur in regions of low baseline metabolic rate (also associated with low perfusion and, thus, greater potential temperature increase due to high local SAR), such that PET signal in these areas remains comparatively low. Maximum relative increases in regions of high metabolic rate (and also high perfusion: heart, thyroid, brain, etc.) are affected mostly by the relatively small increase in core body temperature and thus are not affected greatly (10% maximum increase).

Conclusions: Even for worst-case heating, little effect of MR-induced heating is expected on 18FDG PET images during PET/MR for many clinically relevant applications. For quantitative, dynamic MR/PET studies requiring high SAR for extended periods, it is hoped that methods like those introduced here can help account for such potential effects in design of a given study, including selection of reference locations that should not experience notable increase in temperature.
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http://dx.doi.org/10.1002/mp.12046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538360PMC
February 2017

Central noradrenaline transporter availability in highly obese, non-depressed individuals.

Eur J Nucl Med Mol Imaging 2017 Jun 9;44(6):1056-1064. Epub 2017 Jan 9.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

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-[C]O-methylreboxetine (MRB) in twenty subjects comprising ten highly obese (body mass index BMI > 35 kg/m), metabolically healthy, non-depressed individuals and ten non-obese (BMI < 30 kg/m) healthy controls.

Results: Overall, we found no significant differences in binding potential (BP) 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 BP in all but one (control) case. Furthermore, inter-regional correlation analyses indicated different BP 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.
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http://dx.doi.org/10.1007/s00259-016-3590-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538358PMC
June 2017

Age-related changes in binding of the D2/3 receptor radioligand [(11)C](+)PHNO in healthy volunteers.

Neuroimage 2016 Apr 11;130:241-247. Epub 2016 Feb 11.

Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.

Objective: Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [(11)C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age.

Methods: Forty-two healthy control subjects (9 females, 33 males; age range 19-55 years) were scanned with [(11)C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BPND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images.

Results: Regional [(11)C](+)PHNO BPND displayed a negative correlation between receptor availability and age in the caudate (r=-0.56, corrected p=0.0008) and putamen (r=-0.45, corrected p=0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions.

Conclusion: In accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [(11)C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.
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http://dx.doi.org/10.1016/j.neuroimage.2016.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808424PMC
April 2016

A scan without evidence is not evidence of absence: Scans without evidence of dopaminergic deficit in a symptomatic leucine-rich repeat kinase 2 mutation carrier.

Mov Disord 2016 Mar 21;31(3):405-9. Epub 2015 Dec 21.

University of British Columbia, Vancouver, BC, Canada.

Introduction: The basis for SWEDD is unclear, with most cases representing PD mimics but some later developing PD with a dopaminergic deficit.

Methods: We studied a patient initially diagnosed with SWEDD (based on (18)F-dopa PET) who developed unequivocal PD associated with a leucine-rich repeat kinase 2 p.G2019S mutation. Repeat multitracer PET was performed at 17 years' disease duration, including (+)[11C]dihydrotetrabenazine, [11C](N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (which binds the serotonin transporter), and (18)F-dopa.

Results: The patient showed bilateral striatal dopaminergic denervation (right putamen 28% of age-matched normal, left putamen 33%). (18)F-dopa uptake was decreased, particularly on the left (mean 31% of normal vs. 45% on the more affected right side). Serotonin transporter binding was relatively preserved in the putamen (right mean 90% of normal, left 81%) and several cortical regions.

Conclusions: SWEDD can occur in genetically determined PD and may, in some cases, be the result of compensatory nondopaminergic mechanisms operating in early disease.
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http://dx.doi.org/10.1002/mds.26450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894497PMC
March 2016

Current Status of Hybrid PET/MRI in Oncologic Imaging.

AJR Am J Roentgenol 2016 Jan 22;206(1):162-72. Epub 2015 Oct 22.

1 Department of Radiology, NYU School of Medicine, 660 First Ave, 2nd Fl, New York, NY 10016.

Objective: This review article explores recent advancements in PET/MRI for clinical oncologic imaging.

Conclusion: Radiologists should understand the technical considerations that have made PET/MRI feasible within clinical workflows, the role of PET tracers for imaging various molecular targets in oncology, and advantages of hybrid PET/MRI compared with PET/CT. To facilitate this understanding, we discuss clinical examples (including gliomas, breast cancer, bone metastases, prostate cancer, bladder cancer, gynecologic malignancy, and lymphoma) as well as future directions, challenges, and areas for continued technical optimization for PET/MRI.
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http://dx.doi.org/10.2214/AJR.15.14968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915069PMC
January 2016

A preliminary study of dopamine D2/3 receptor availability and social status in healthy and cocaine dependent humans imaged with [(11)C](+)PHNO.

Drug Alcohol Depend 2015 Sep 30;154:167-73. Epub 2015 Jun 30.

Department of Psychiatry, Yale University, New Haven, CT, United States.

Background: Previous work in healthy non-human primates and humans has shown that social status correlates positively with dopamine 2/3 receptor (D2/3R) availability imaged with antagonist radioligands and positron emission tomography (PET). Further work in non-human primates suggests that this relationship is disrupted by chronic cocaine administration. This exploratory study examined the relationship between social status and D2/3R availability in healthy (HH) and cocaine dependent (CD) humans using the D3-preferring, agonist radioligand, [(11)C](+)PHNO.

Methods: Sixteen HH and sixteen CD individuals completed the Barratt Simplified Measure of Social Status (BSMSS) and underwent [(11)C](+)PHNO scanning to measure regional brain D2/3R binding potentials (BPND). Correlations between BPND and BSMSS scores were then assessed within each group.

Results: Within HH and CD groups, inverse associations between BSMSS score and BPND were observed in the substantia nigra/ventral tegmental area (SN/VTA) and the ventral striatum, and for the CD group alone, the amygdala. After adjusting for body mass index and age, negative correlations remained significant in the SN/VTA for HH and in the amygdala for CD subjects.

Conclusion: These preliminary data utilizing a dopamine agonist tracer demonstrate, for the first time, an inverse association between social status and D2/3R availability in the D3R rich extrastriatal regions of HH and CD humans.
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http://dx.doi.org/10.1016/j.drugalcdep.2015.06.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536182PMC
September 2015

Test-retest reproducibility of the metabotropic glutamate receptor 5 ligand [¹⁸F]FPEB with bolus plus constant infusion in humans.

Eur J Nucl Med Mol Imaging 2015 Sep 5;42(10):1530-41. Epub 2015 Jun 5.

PET Center, Department of Diagnostic Radiology, Yale School of Medicine, 801 Howard Avenue, PO Box 208048, New Haven, CT, 06520-8048, USA,

Purpose: [(18)F]FPEB is a promising PET radioligand for the metabotropic glutamate receptor 5 (mGluR5), a potential target for the treatment of neuropsychiatric diseases. The purpose of this study was to evaluate the test-retest reproducibility of [(18)F]FPEB in the human brain.

Methods: Seven healthy male subjects were scanned twice, 3 - 11 weeks apart. Dynamic data were acquired using bolus plus infusion of 162 ± 32 MBq [(18)F]FPEB. Four methods were used to estimate volume of distribution (V T): equilibrium analysis (EQ) using arterial (EQA) or venous input data (EQV), MA1, and a two-tissue compartment model (2 T). Binding potential (BP ND) was also estimated using cerebellar white matter (CWM) or gray matter (CGM) as the reference region using EQ, 2 T and MA1. Absolute test-retest variability (aTRV) of V T and BP ND were calculated for each method. Venous blood measurements (C V) were compared with arterial input (C A) to examine their usability in EQ analysis.

Results: Regional V T estimated by the four methods displayed a high degree of agreement (r (2) ranging from 0.83 to 0.99 among the methods), although EQA and EQV overestimated V T by a mean of 9 % and 7 %, respectively, compared to 2 T. Mean values of aTRV of V T were 11 % by EQA, 12 % by EQV, 14 % by MA1 and 14 % by 2 T. Regional BP ND also agreed well among the methods and mean aTRV of BP ND was 8 - 12 % (CWM) and 7 - 9 % (CGM). Venous and arterial blood concentrations of [(18)F]FPEB were well matched during equilibrium (C V = 1.01 · C A, r (2) = 0.95).

Conclusion: [(18)F]FPEB binding shows good TRV with minor differences among analysis methods. Venous blood can be used as an alternative for input function measurement instead of arterial blood in EQ analysis. Thus, [(18)F]FPEB is an excellent PET imaging tracer for mGluR5 in humans.
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http://dx.doi.org/10.1007/s00259-015-3094-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467218PMC
September 2015

Imaging human brown adipose tissue under room temperature conditions with (11)C-MRB, a selective norepinephrine transporter PET ligand.

Metabolism 2015 Jun 5;64(6):747-55. Epub 2015 Mar 5.

Departments of Radiology and Psychiatry, New York University School of Medicine. Electronic address:

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°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.
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http://dx.doi.org/10.1016/j.metabol.2015.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408242PMC
June 2015

Quantitative graphical analysis of simultaneous dynamic PET/MRI for assessment of prostate cancer.

Clin Nucl Med 2015 Apr;40(4):e236-40

From the *Department of Radiology, and †Division of Urologic Oncology, Department of Urology, NYU Langone Medical Center, New York, NY.

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/cm3 per minute). In 1 case appearing reversible, tumor had higher VT than benign using reversible graphical analysis (0.68 vs 0.52 mL/cm3).

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.
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http://dx.doi.org/10.1097/RLU.0000000000000673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352122PMC
April 2015

A pilot study in epilepsy patients using simultaneous PET/MR.

Am J Nucl Med Mol Imaging 2014 15;4(5):459-70. Epub 2014 Aug 15.

Department of Neurology, New York University School of Medicin New York, NY, USA.

Integrated PET/MR with simultaneous acquisition may improve the identification of pathologic findings in patients. This pilot study evaluated metabolic activity differences between epilepsy patients and healthy controls and directly correlated FDG uptake with MR regional abnormality. Epilepsy patients (n=11) and controls (n=6) were imaged on a whole-body simultaneous PET/MR scanner. After FDG injection, simultaneous images were acquired for 60 minutes. Statistical analyses on SUV values (over 117 brain regions, including left and right, for 96 cortical and 21 subcortical regions) derived from three normalization methods, by individual subject's mean cortical, white matter or global brain, were compared between groups. The asymmetry was compared. T2, T1 and PET co-registered images were also used for lesion detection and correlation of PET and MR regional abnormality. Left and right postcentral gyri were found to be consistently hypermetabolic regions, while right temporal pole and planum polare were consistently hypometabolic regions by all three normalization methods. Using the asymmetry index (AI > 10% or SUV ratios > 1.2), more metabolic asymmetry regions were detected in patients than in controls, with 96.2% agreement. The presence of hippocampal abnormalities or cortical tubers detected via T2 FLAIR in patients correlated well with the hypometabolism detected via FDG-PET. Our results showed specific patterns of metabolic abnormality and asymmetry over 117 brain regions in epilepsy patients, as compared to controls, suggest that simultaneous PET/MR imaging provides a useful tool to help understand etiopathogenesis and localize seizure foci.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138140PMC
August 2014

Parametric Imaging and Test-Retest Variability of ¹¹C-(+)-PHNO Binding to D₂/D₃ Dopamine Receptors in Humans on the High-Resolution Research Tomograph PET Scanner.

J Nucl Med 2014 Jun 14;55(6):960-6. Epub 2014 Apr 14.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; and.

Unlabelled: (11)C-(+)-4-propyl-9-hydroxynaphthoxazine ((11)C-(+)-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 (11)C-(+)-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 (11)C-(+)-PHNO scans for the same subject were separated by 5.4 ± 0.7 h. After compartment models were evaluated, (11)C-(+)-PHNO volumes of distribution (V(T)) and binding potentials relative to the concentration of tracer in plasma (BP(P)), nondisplaceable tracer in tissue (BP(ND)), and free tracer in tissue (BP(F)) were quantified using the multilinear analysis MA1 method, with the cerebellum as the reference region. Parametric images of BP(ND) were also computed using the simplified reference tissue model (SRTM) and SRTM2.

Results: The test-retest variability of (11)C-(+)-PHNO BP(ND) 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 BP(ND) was present in the substantia nigra (-14% ± 15%). Because of the relatively fast kinetics, low-noise BP(ND) parametric images were obtained with both SRTM and SRTM2 without spatial smoothing.

Conclusion: (11)C-(+)-PHNO can be used to compute low-noise parametric images in both D2- and D3-rich regions in humans.
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http://dx.doi.org/10.2967/jnumed.113.132928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201637PMC
June 2014

Dopamine D₃ receptor alterations in cocaine-dependent humans imaged with [¹¹C](+)PHNO.

Drug Alcohol Depend 2014 Jun 20;139:100-5. Epub 2014 Mar 20.

Department of Radiology and Psychiatry, New York University School of Medicine, New York, NY, USA.

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.
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http://dx.doi.org/10.1016/j.drugalcdep.2014.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071607PMC
June 2014

Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice.

Neuron 2014 Jan;81(1):77-90

Department of Psychiatry, Yale University School of Medicine.

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.
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http://dx.doi.org/10.1016/j.neuron.2013.10.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894588PMC
January 2014

Decreased norepinephrine transporter availability in obesity: Positron Emission Tomography imaging with (S,S)-[(11)C]O-methylreboxetine.

Neuroimage 2014 Feb 10;86:306-10. Epub 2013 Oct 10.

Department of Psychiatry and Radiology, New York University, New York, NY, USA. Electronic address:

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)-[(11)C]O-methylreboxetine ([(11)C]-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.
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http://dx.doi.org/10.1016/j.neuroimage.2013.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947246PMC
February 2014

Association of posttraumatic stress disorder with reduced in vivo norepinephrine transporter availability in the locus coeruleus.

JAMA Psychiatry 2013 Nov;70(11):1199-1205

Departments of Psychiatry and Radiology, New York University School of Medicine, New York.

Importance: Animal data suggest that chronic stress is associated with a reduction in norepinephrine transporter (NET) availability in the locus coeruleus. However, it is unclear whether such models are relevant to posttraumatic stress disorder (PTSD), which has been linked to noradrenergic dysfunction in humans.

Objectives: To use positron emission tomography and the radioligand [11C]methylreboxetine to examine in vivo NET availability in the locus coeruleus in the following 3 groups of individuals: healthy adults (HC group), adults exposed to trauma who did not develop PTSD (TC group), and adults exposed to trauma who developed PTSD (PTSD group) and to evaluate the relationship between NET availability in the locus coeruleus and a contemporary phenotypic model of PTSD symptoms.

Design, Setting, And Participants: Cross-sectional positron emission tomography study under resting conditions at academic and Veterans Affairs medical centers among 56 individuals in the following 3 study groups: HC (n = 18), TC (n = 16), and PTSD (n = 22).

Main Outcomes And Measures: The [11C]methylreboxetine-binding potential of NET availability in the locus coeruleus and the severity of PTSD symptoms assessed using the Clinician-Administered PTSD Scale.

Results: The PTSD group had significantly lower NET availability than the HC group (41% lower, Cohen d = 1.07). NET availability did not differ significantly between the TC and HC groups (31% difference, Cohen d = 0.79) or between the TC and PTSD groups (15% difference, Cohen d = 0.28). In the PTSD group, NET availability in the locus coeruleus was independently positively associated with the severity of anxious arousal (ie, hypervigilance) symptoms (r = 0.52) but not with any of the other PTSD symptom clusters.

Conclusions And Relevance: These results suggest that PTSD is associated with significantly reduced NET availability in the locus coeruleus and that greater NET availability in this brain region is associated with increased severity of anxious arousal symptoms in individuals with PTSD.
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http://dx.doi.org/10.1001/jamapsychiatry.2013.399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026855PMC
November 2013

Determination of in vivo Bmax and Kd for 11C-GR103545, an agonist PET tracer for κ-opioid receptors: a study in nonhuman primates.

J Nucl Med 2013 Apr 19;54(4):600-8. Epub 2013 Feb 19.

PET Center, Department of Diagnostic Radiology, Yale University, New Haven, CT 06520, USA.

Unlabelled: The κ-opioid receptors (KOR) are involved in mood disorders and addictive conditions. In vivo imaging studies of this receptor in humans have not been reported because of the lack of a selective ligand. We used a recently developed selective KOR agonist tracer, (11)C-GR103545, and performed a study in rhesus monkeys to estimate the in vivo receptor concentration (Bmax) and dissociation equilibrium constant (Kd).

Methods: Four rhesus monkeys underwent 12 scans with (11)C-GR103545 on a PET scanner under baseline and self-blocking conditions. The injected mass was 0.042 ± 0.014 μg/kg for the baseline scans and ranged from 0.16 to 0.3 μg/kg for the self-blocking scans. The radiotracer was administered in a bolus-plus-infusion protocol, and cerebellum was used as the reference region in kinetic analysis. Binding potential (BPND) values were computed as [(CROI/CREF) - 1], where CROI and CREF are the mean of the radioactivity concentrations from 90 to 120 min after tracer administration in a given region of interest (ROI) and in the cerebellum. In 6 scans, arterial input functions and free fraction in plasma (fp) were measured. In addition, a 2-tissue-compartment model was used to compute the volume of distribution in the cerebellum (VT_REF), which was then used to estimate the free-to-nondisplaceable concentration ratio (fND) as fp/VT_REF. A Scatchard plot was used to estimate Bmax, and Kd(ND) = Kd/fND, the Kd value with respect to the cerebellar concentration. Individual data were first analyzed separately and then pooled together. When Kd(ND) was allowed to vary among ROIs, results were variable; therefore, Kd(ND) was constrained to be constant across ROIs, whereas Bmax was allowed to be ROI-dependent and animal-dependent.

Results: A global estimate of 1.72 nM was obtained for Kd(ND). Estimated Bmax ranged from 0.3 to 6.1 nM across ROIs and animals. The Kd estimate of 0.048 nM, obtained by correcting Kd(ND) by the factor fND, was in good agreement with the half maximal inhibitory concentration (IC50) of 0.018 nM determined from functional assays in rabbit vas deferens and inhibition constant (Ki) of 0.02 nM measured in radioligand competition assays using cloned human receptors. On the basis of these data, a suitable tracer dose of 0.02 μg/kg was selected for use in humans.

Conclusion: The use of a bolus-plus-infusion protocol with the KOR agonist tracer (11)C-GR103545 permitted the successful estimation of Bmax and Kd(ND) in vivo. On the basis of the estimated Kd value, a tracer dose of 1.4 μg (3.38 nmol) for an average body weight of 70 kg was chosen as the mass dose limit in human studies using this novel agonist radiotracer.
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http://dx.doi.org/10.2967/jnumed.112.112672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775350PMC
April 2013

Test-retest reproducibility of [11C]-(+)-propyl-hexahydro-naphtho-oxazin positron emission tomography using the bolus plus constant infusion paradigm.

Mol Imaging 2013 Mar-Apr;12(2):77-82

Department of Psychiatry, Yale University School of Medicine, Yale University, New Haven, CT 06516, USA.

We examined the reproducibility of using the constant infusion paradigm for equilibrium measurement of D2/3 receptors using [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) positron emission tomography (PET). Six subjects were scanned with a bolus plus constant infusion (Kbol = 80 minutes) of [11C]-(+)-PHNO. Binding potential (BPND) was computed using the equilibrium approach and compared to a simplified reference tissue model (SRTM). The rate of change in the concentration-activity curve from 60 to 90 minutes was -5 ± 13%/h in the caudate, putamen, substantia nigra, thalamus, and cerebellum but was 15 ± 15%/h in the ventral striatum and pallidum. Test-retest variability was lower in striatal compared to extrastriatal regions (4 ± 8% vs -8 ± 22%, respectively) using the equilibrium approach, with comparable results with SRTM. The equilibrium ratio and SRTM yielded reliable BPND estimates (intraclass correlation coefficient = 0.88 and 0.82, respectively). These studies support the reproducibility of the bolus plus constant infusion paradigm with [11C]-(+)-PHNO PET.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699696PMC
August 2013

Kinetic analysis of the metabotropic glutamate subtype 5 tracer [(18)F]FPEB in bolus and bolus-plus-constant-infusion studies in humans.

J Cereb Blood Flow Metab 2013 Apr 19;33(4):532-41. Epub 2012 Dec 19.

Yale PET Center, Department of Diagnostic Radiology, Yale University, New Haven, CT, USA.

[(18)F]FPEB is a positron emission tomography tracer which, in preclinical studies, has shown high specificity and selectivity toward the metabotropic glutamate receptor 5 (mGluR5). It possesses the potential to be used in human studies to evaluate mGluR5 function in a range of neuropsychiatric disorders, such as anxiety and Fragile X syndrome. To define optimal scan methodology, healthy human subjects were scanned for 6 hours following either a bolus injection (n=5) or bolus-plus-constant-infusion (n=5) of [(18)F]FPEB. Arterial blood samples were collected and parent fraction measured by high-performance liquid chromatography (HPLC) to determine the metabolite-corrected plasma input function. Time activity curves were extracted from 13 regions and fitted by various models to estimate V(T) and BPND. [(18)F]FPEB was well fitted by the two-tissue compartment model, MA1 (t*=30), and MRTM (using cerebellum white matter as a reference). Highest V(T) values were observed in the anterior cingulate and caudate, and lowest V(T) values were observed in the cerebellum and pallidum. For kinetic modeling studies, VT and BPND were estimated from bolus or bolus-plus-constant-infusion scans as short as 90 minutes. Bolus-plus-constant-infusion of [(18)F]FPEB reduced intersubject variability in V(T) and allowed equilibrium analysis to be completed with a 30-minute scan, acquired 90-120 minutes after the start of injection.
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http://dx.doi.org/10.1038/jcbfm.2012.195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618388PMC
April 2013

Age effects on serotonin receptor 1B as assessed by PET.

J Nucl Med 2012 Sep 31;53(9):1411-4. Epub 2012 Jul 31.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Unlabelled: Previous imaging studies have suggested that there is an age-related decline in brain serotonin (5-hydroxytryptamine) measures in healthy subjects. This paper addresses whether the availability of 5-hydroxytryptamine receptor 1B (5-HT(1B)) is seen to decrease with aging via PET imaging.

Methods: Forty-eight healthy control subjects (mean age ± SD, 30 ± 10 y; age range, 18-61 y; 33 men, 15 women) underwent (11)C-P943 scanning on a high-resolution PET tomograph. Regions were examined with and without gray matter masking, the latter in an attempt to control for age-related gray matter atrophy on nondisplaceable binding potential (BP(ND)) as determined by a validated multilinear reference tissue model.

Results: 5-HT(1B) BP(ND) decreased in the cortex at an average rate of 8% per decade without and 9% with gray matter masking. A negative association with age was also observed in all individual cortical regions. Differences in the putamen and pallidum (positive association) were significant after adjustment for multiple comparisons. No sex- or race-related effects on 5-HT(1B) BP(ND) were found in any regions.

Conclusion: These findings indicate that age is a relevant factor for 5-HT(1B) in the cortex of healthy adults.
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http://dx.doi.org/10.2967/jnumed.112.103598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690814PMC
September 2012

Age effects on serotonin receptor 1B as assessed by PET.

J Nucl Med 2012 Sep 31;53(9):1411-4. Epub 2012 Jul 31.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Unlabelled: Previous imaging studies have suggested that there is an age-related decline in brain serotonin (5-hydroxytryptamine) measures in healthy subjects. This paper addresses whether the availability of 5-hydroxytryptamine receptor 1B (5-HT(1B)) is seen to decrease with aging via PET imaging.

Methods: Forty-eight healthy control subjects (mean age ± SD, 30 ± 10 y; age range, 18-61 y; 33 men, 15 women) underwent (11)C-P943 scanning on a high-resolution PET tomograph. Regions were examined with and without gray matter masking, the latter in an attempt to control for age-related gray matter atrophy on nondisplaceable binding potential (BP(ND)) as determined by a validated multilinear reference tissue model.

Results: 5-HT(1B) BP(ND) decreased in the cortex at an average rate of 8% per decade without and 9% with gray matter masking. A negative association with age was also observed in all individual cortical regions. Differences in the putamen and pallidum (positive association) were significant after adjustment for multiple comparisons. No sex- or race-related effects on 5-HT(1B) BP(ND) were found in any regions.

Conclusion: These findings indicate that age is a relevant factor for 5-HT(1B) in the cortex of healthy adults.
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http://dx.doi.org/10.2967/jnumed.112.103598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690814PMC
September 2012