記述言語：英語  

DOI： 10.2967/jnumed.122.263838

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12888-022-03866-7

PubMed

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記述言語：英語  

DOI： 10.1186/s13550-022-00882-2

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記述言語：英語  

DOI： 10.1021/acschemneuro.1c00730

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The number of suicides in Japan decreased during the period from 2012 through 2019. Because data on factors associated with this decline are limited, we conducted a retrospective longitudinal study of psychiatric diagnoses of serious suicide attempters before 2012 and after 2019. METHODS: Serious suicide attempters admitted to the critical care medicine (CCM) department of Nippon Medical School Hospital between 2006 and 2017 were included and classified as those before and after the suicide decline in 2012. Chi-square test and residual analysis were used to analyze changes in the proportion of suicide attempters among all patients admitted to CCM and to examine differences in the proportion of psychiatric diagnoses. RESULTS: The proportion of suicide attempters among CCM hospitalized patients decreased overall (χ2 (1) =18.29, p<.01). The proportion of psychiatric diagnoses changed significantly (χ2 (8) =62.21, p<0.001); specifically, it decreased for schizophrenia (residual: -2.28), depressive disorders (residual: -5.39), persistent mood disorders (residual: -3.58), and reaction to stress disorders (residual: -2.73). Depressive disorders decreased and had a large contribution ratio in both sexes. CONCLUSIONS: The decrease in the proportion of attempted suicides among patients admitted to CCM was consistent with the decline in suicides in Japan. Analysis by psychiatric diagnosis confirmed a significant decrease in the proportion of suicide attempts associated with depressive disorders, schizophrenia, and reaction to stress disorders, which were the most common disorders associated with attempted suicide. Depressive disorders made the greatest contribution to the reduction in suicide attempts.

DOI： 10.1272/jnms.JNMS.2022_89-405

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fpsyt.2022.799319

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Electroconvulsive therapy (ECT) is an effective treatment for depressive disorders, although its molecular mechanism of action is unknown. The serotonin 1B (5-HT) receptor is a potential target for treatment of depression and low 5-HT receptor binding in limbic regions has been reported in previous positron emission tomography (PET) studies of depression.The objective of this longitudinal PET study was to examine the effect of ECT for depression on 5-HT receptor binding. Fifteen hospitalized patients with major depressive episodes were examined with PET and the 5-HT receptor selective radioligand [C]AZ10419369, before and after ECT. Fifteen controls matched for age and sex were examined. Limbic regions with previously reported low 5-HT receptor binding in depression and a dorsal brain stem region were selected.Thirteen patients completed the study according to protocol. Eleven out of thirteen patients responded to ECT. 5-HT receptor binding in hippocampus increased with 30 % after ECT (p=0.021). Using linear mixed effects modelling, we observed increases in 5-HT receptor binding following ECT with a moderate to large effect size, which did not differ significantly between regions.

DOI： 10.1016/j.jad.2021.07.060

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記述言語：日本語  

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記述言語：英語  

Anodal transcranial Direct Current Stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) is known as one of the useful applications for improving depressive symptoms or cognitive performance. Antidepressive effects by anodal tDCS over the left DLPFC are expected, but the neural mechanisms of these effects are still unclear. Further, in depression, reduced performance and left prefrontal hypofunction during verbal fluency task (VFT) are generally known. However, few studies have examined the effect of tDCS on the language-related cerebral network. We aimed to investigate whether anodal tDCS at the left DLPFC affects cognitive performance and the neural basis of verbal fluency.Nineteen healthy volunteers participated in this study. The effects of tDCS on cognitive behavior and cerebral function were evaluated by 1) performance and accuracy of implicit/explicit motor learning task (serial reaction time task: SRTT/sequential finger-tapping task: SFTT), and 2) cerebral activation while the subjects were performing VFT by using a functional MRI protocol of a randomized sham-controlled, within-subjects cross-over design.Reaction times of implicit motor learning task were

DOI： 10.1111/pcn.13208

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語  

DOI： 10.1007/s00213-020-05698-3

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記述言語：英語  

DOI： 10.1158/1078-0432.CCR-19-1871

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記述言語：英語  

DOI： 10.1016/j.bja.2020.08.052

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/pcn.13020

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記述言語：英語  

DOI： 10.1021/acschemneuro.0c00161

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記述言語：英語  

The metabotropic glutamate receptor subtype mGluR5 has been proposed as a potential drug target for CNS disorders such as anxiety, depression, Parkinson's disease and epilepsy. The AstraZeneca compound AZD9272 has previously been labeled with carbon-11 and used as a PET radioligand for mGluR5 receptor binding. The molecular structure of AZD9272 allows to label the molecule with fluorine-18 without altering the structure. The aim of this study was to develop fluorine-18 analogue of AZD9272 and to examine its binding distribution in the non-human primate brain in vivo as well as to obtain whole body radiation dosimetry. [18F]AZD9272 was successfully synthesized from nitro precursor. The radioligand was stable, with a radiochemical purity of >99% at 2h after formulation in a sterile phosphate buffered solution (pH = 7.4). After injection of [18F]AZD9272 in two cynomolgus monkeys the maximum whole brain radioactivity concentration was 4.9-6.7 % of injected dose (n=2) and PET images showed a pattern of regional radioactivity consistent with that previously obtained for [11C]AZD9272. The percentage of parent radioligand in plasma was 59 and 64% (n=2) at 120 min after injection of [18F]AZ

DOI： 10.1021/acschemneuro.9b00680

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記述言語：英語  

DOI： 10.1007/s00259-020-04739-5

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記述言語：英語  

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記述言語：英語  

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記述言語：日本語  

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記述言語：英語  

Over the last decade, a few radioligands have been developed for PET imaging of brain 5-HT receptors. The 5-HT receptor is a G-protein-coupled receptor (GPCR) that exists in two different agonist affinity states. An agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-HT, than an antagonist ligand. It is of interest to know whether the intrinsic activity of a PET radioligand for the 5-HT receptor impacts on its ability to detect changes in endogenous synaptic 5-HT density. Three high-affinity C-labeled 5-HT PET radioligands with differing intrinsic activity were applied to PET measurements in cynomolgus monkey to evaluate their sensitivity to be displaced within the brain by endogenous 5-HT. For these experiments, fenfluramine was pre-administered at two different doses (1.0 and 5.0 mg/kg, i.v.) to induce synaptic 5-HT release.A dose-dependent response to fenfluramine was detected for all three radioligands. At the highest dose of fenfluramine (5.0 mg/kg, i.v.), reductions in specific binding in the occipital cortex increased with radioligand agonist efficacy, reaching 61% for [C]3. The most antagonistic radioligand show

DOI： 10.1186/s13550-019-0570-1

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記述言語：英語  

DOI： 10.1016/j.neuropharm.2019.107809

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記述言語：英語  

DOI： 10.1021/acs.jmedchem.9b00847

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記述言語：英語  

DOI： 10.1016/j.bmcl.2019.06.037

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記述言語：英語  

DOI： 10.2967/jnumed.118.217372

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記述言語：英語  

DOI： 10.1016/j.bmcl.2019.04.040

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記述言語：英語  

DOI： 10.1007/s11307-018-1257-0

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記述言語：英語  

DOI： 10.1093/ijnp/pyz003

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記述言語：英語  

DOI： 10.1093/ijnp/pyy089

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記述言語：日本語  

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記述言語：英語  

DOI： 10.1016/j.nucmedbio.2019.10.003

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記述言語：英語  

DOI： 10.1021/acschemneuro.8b00236

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記述言語：英語  

DOI： 10.1007/s00259-018-4012-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/ijnp/pyy004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer New York LLC  

Purpose: Positron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BPND) of [11C]raclopride in NHP. Procedures: Three cynomolgus monkeys underwent two to three PET measurements with [11C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BPND in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region. Results: In each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman’s ρ = − 0.79, p = 0.03), but not with BPND (ρ = − 0.25, p = 0.55). Conclusions: These data suggest that sevoflurane affects the shape of TACs but has no evident effect on BPND in consecutive PET measurements.

DOI： 10.1007/s11307-017-1120-8

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記述言語：英語  

DOI： 10.1021/acs.jmedchem.7b01769

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記述言語：英語  

DOI： 10.1186/s13550-017-0301-4

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記述言語：英語  

DOI： 10.1002/anie.201708744

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NUCLEAR MEDICINE INC  

Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (S,S)-C-11-MRB and (S,S)-F-18-FMeNER-D-2, have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using PET in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with (S,S)-C-11-MRB and defluorination with (S,S)-F-18-FMeNER-D-2, which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated F-18 radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including the cerebral cortex using (S,S)-F-18-FMeNER-D-2 PET. Methods: We analyzed our previous (S,S)-F-18-FMeNER-D-2 PET data of 10 healthy volunteers dynamically acquired for 240min with arterial blood sampling. The effects of defluorination on the NET quantification in the superficial cerebral cortex was evaluated by establishing a time stability of NET density estimations with an arterial input 2-tissue-compartment model, which guided the less-invasive reference tissue model and area under the time-activity curve methods to accurately quantify NET density in all brain regions including the cerebral cortex. Results: Defluorination of (S,S)-F-18-FMeNER-D-2 became prominent toward the latter half of the 240-min scan. Total distribution volumes in the superficial cerebral cortex increased with the scan duration beyond 120 min. We verified that 90-min dynamic scans provided a sufficient amount of data for quantification of NET density unaffected by defluorination. Reference tissue model binding potential values from the 90-min scan data and area under the time-activity curve ratios of 70-to 90-min data allowed for the accurate quantification of NET density in the cerebral cortex. Conclusion: We have established methods of quantification of NET densities in the brain including the cerebral cortex unaffected by defluorination using (S,S)-F-18-FMeNER-D-2. These results suggest that we can accurately quantify NET density with a 90-min (S,S)-F-18-FMeNER-D-2 scan in broad brain areas.

DOI： 10.2967/jnumed.116.178913

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.dmpk.2016.07.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood.
We examined 32 healthy individuals using positron emission tomography (PET) and [C-11]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [C-11]PBR28 in brain and in blood cells.
TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbi.2016.01.019

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Sixteen healthy volunteers were enrolled and divided into four groups according to the single administration of 10 mg or 20 mg escitalopram, 50 mg sertraline, or 20 mg paroxetine. Four positron emission tomography scans with [C-11]DASB were performed on each subject, the first prior to taking the drug, followed by the others at 4, 24, and 48 h after. Serotonin transporter occupancies of the drugs at each time point were calculated. All drugs showed maximum occupancy at 4 h after dosing and then decreasing occupancies with time. Escitalopram and sertraline showed high occupancies of 69.1-77.9% at 4 h, remaining at 52.8-57.8% after 48 h. On the other hand, paroxetine showed relatively low occupancy of 44.6%, then decreasing to 10.3% at 48 h. Escitalopram (both 10 mg and 20 mg) and sertraline (50 mg) showed high and sustained occupancy. Paroxetine (20 mg) showed relatively low and rapidly decreasing occupancy, possibly due to the low plasma concentration by single dosing schedule. Applying the reported concentration of multiple dosing, 20 mg paroxetine will induce over 80% occupancy. The present study suggested that these drugs and doses would be sufficient for the treatment of depression. (C) 2016 Published by Elsevier Ireland Ltd.

DOI： 10.1016/j.pscychresns.2016.03.006

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Mazindol, an appetite suppressant, inhibits the reuptake of dopamine in the synaptic cleft. It has been considered that mazindol might enhance dopamine transmission in the human brain. However, there has been no study that investigated the extracellular dopamine concentration in vivo.
Using positron emission tomography (PET), we aimed to measure the effect of mazindol on the extracellular dopamine concentration and to evaluate how mazindol affects the dopamine system in the healthy human brain.
Eleven healthy individuals (six males, five females, age 30.9 +/- 4.9 years) were enrolled in this study. Each participant was scanned with [C-11]raclopride on 1 day without any medicine as baseline condition, and on another day with mazindol as drug condition. In the drug condition, participants took mazindol 0.5 mg (N = 5) or 1.5 mg (N = 6) 2 h before the PET scan. Plasma concentrations of mazindol were measured before the injection of [C-11]raclopride, and urine concentrations of mazindol were measured after the scan.
After taking mazindol, the calculated decrease in binding potential (Delta BP) in the striatum was 1.74 % for 0.5 mg and 8.14 for 1.5 mg, and the correlation with the blood concentration of mazindol was significant (P = 0.0016, R (2) = 0.69). Delta BP was not significantly correlated with the urine concentration of mazindol (P = 0.84, R (2) = 0.005).
Mazindol increased the extracellular concentration of dopamine in the human brain, and its effect was dose dependent. A single administration of mazindol, even at usual dosage, elevated dopamine concentration similarly to other addictive drugs, suggesting that the risk of dependence may increase with the mazindol dose.

DOI： 10.1007/s00213-013-3392-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CAMBRIDGE UNIV PRESS  

Tramadol is used for the treatment of pain, and it is generally believed to activate the -opioid receptor and inhibit serotonin (5-HT) and norepinephrine (NE) transporters. Recent findings from animal experiments suggest that 5-HT reuptake inhibition in brain is related to pain reduction. However, there has been no report of 5-HT transporter (5-HTT) occupancy by tramadol at clinical doses in humans. In the present study, we investigated 5-HTT occupancy by tramadol in five subjects receiving various doses of tramadol by using positron emission tomography (PET) scanning with the radioligand [C-11]DASB. Our data showed that mean 5-HTT occupancies in the thalamus by single doses of tramadol were 34.7% at 50mg and 50.2% at 100mg. The estimated median effective dose (ED50) of tramadol was 98.1mg, and the plasma concentration was 0.33g/ml 2h after its administration; 5-HTT occupancy by tramadol was dose-dependent. We estimated 5-HTT occupancy at 78.7% upon taking an upper limit dose (400mg) of tramadol. The results of the present study support the finding that 5-HTT inhibition is involved in the mechanism underlying the analgesic effect of tramadol in humans, and a clinical dose of tramadol sufficiently inhibits 5-HTT reuptake; this inhibition is similar to that shown by selective serotonin reuptake inhibitors (SSRIs).

DOI： 10.1017/S1461145713001764

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1017/S1461145713001612

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12149-013-0798-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Purpose The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The F-18-labeled amyloid tracer, [F-18]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1,3-benzoxazol-6-yl)oxy]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [C-11]Pittsburgh compound B (PIB) and [F-18]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared.
Methods Two PET scans, one of each with [C-11]PIB and [F-18]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation.
Results No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [F-18]FACT studies without partial volume correction, while significant differences were observed in [C-11]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [F-18]FACT studies as well as [C-11]PIB. Relatively lower uptakes of [C-11]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [F-18]FACT. Relatively higher uptake of [C-11]PIB in distribution was observed in the frontal and parietal cortices.
Conclusion Since [F-18]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [C-11]PIB and [F-18]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic and histochemical assays of postmortem AD brain sections.

DOI： 10.1007/s00259-013-2620-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹⁸F]FMeNER-D₂ to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED₅₀) and concentration (EC₅₀) required to induce 50% occupancy was 65.9 mg/d a

DOI： 10.1017/S1461145713001521

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1017/S1461145713001521

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記述言語：日本語   出版者・発行元：(株)医学書院  

日本では,自殺率が高止まりを続けていることから,自殺対策基本法と自殺総合対策大綱が施行・策定され,厚生労働省は,自殺未遂者対策に関連して救急医療従事者を対象とした自殺未遂者ケアのための研修会を実施している。筆者らは,2012年1月から2013年3月の期間に当該の研修会に参加した224名を対象に質問紙を用いた調査を行い,自殺予防対策に関する正しい知識と適切な態度を問うた。その結果,回答者の多くに,80%以上の正答率が示され,知識の設問に比して態度の設問において有意に高い正答率が得られた。また,自殺の予防可能性については97.0%が好ましい回答を示した。一方で,自殺と精神疾患の関連に関する理解の不足や自殺念慮を確認することへの躊躇などが明らかになった。今後,自殺を低減させていくためには,専門教育・専門職生涯教育における自殺予防の導入,そして効果的な自殺予防教育プログラムの開発が必要と考えられた。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00749&link_issn=&doc_id=20140128110008&doc_link_id=10.11477%2Fmf.1405102636&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1405102636&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.

DOI： 10.1017/S1461145712001009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CAMBRIDGE UNIV PRESS  

Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported &gt;80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [C-11]DASB and (S,S)-[F-18]FMeNER-D-2, in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED50 was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.

DOI： 10.1017/S1461145712001009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Blonanserin is a novel antipsychotic with high affinities for dopamine D-2 and 5-HT2A receptors, and it was recently approved for the treatment of schizophrenia in Japan and Korea. Although double-blind clinical trials have demonstrated that blonanserin has equal efficacy to risperidone, and with a better profile especially with respect to prolactin elevation, its profile of in vivo receptor binding has not been investigated in patients with schizophrenia. Using positron emission tomography (PET), we measured striatal and extrastriatal dopamine D-2 receptor occupancy by blonanserin in 15 patients with schizophrenia treated with fixed doses of blonanserin (ie, 8, 16, and 24 mg/d) for at least 4 weeks before PET scans, and in 15 healthy volunteers. Two PET scans, 1 with [C-11]raclopride for the striatum and 1 with [C-11]FLB 457 for the temporal cortex and pituitary, were performed on the same day. Striatal dopamine D2 receptor occupancy by blonanserin was 60.8% (3.0%) [mean (SD)] at 8 mg, 73.4% (4.9%) at 16 mg, and 79.7% (2.3%) at 24 mg. The brain/plasma concentration ratio calculated from D-2 receptor occupancy in the temporal cortex and pituitary was 3.38, indicating good blood-brain barrier permeability. This was the first study to show clinical daily dose amounts of blonanserin occupying dopamine D-2 receptors in patients with schizophrenia. The clinical implications obtained in this study were the optimal therapeutic dose range of 12.9 to 22.1 mg/d of blonanserin required for 70% to 80% dopamine D-2 receptor occupancy in the striatum, and the good blood-brain barrier permeability that suggested a relatively lower risk of hyperprolactinemia.

DOI： 10.1097/JCP.0b013e3182825bce

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記述言語：英語  

DOI： 10.1111/pcn.12004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

The serotonin system is involved in many physiological functions and clinical conditions. Serotonergic neurons originate from the raphe nuclei in the brainstem, and reliable estimates of receptor/transporter availability in the raphe in vivo are thus of interest. Though positron emission tomography (PET) can be used to quantify receptor distribution in the brain, high noise levels prevent reliable estimation of radioligand binding in small regions such as the raphe. For this purpose, parametric imaging in combination with high-resolution PET systems may provide images with reduced noise levels and sufficient contrast for reliable quantification. This study examined the potential to evaluate radioligand binding in brainstem nuclei, and assessed the effect of improved resolution on the outcome measures.
For comparative purposes, radioligand binding was measured with an ECAT EXACT HR PET system (resolution about 4.5 mm FWHM) and a high-resolution research tomograph (HRRT) system (resolution about 1.5 mm FWHM). Six subjects were examined with both systems on the same day using the serotonin transporter radioligand [C-11]MADAM. Parametric images of binding potential (BP (ND)) were obtained using a wavelet-aided approach. Regions of interest (ROIs) were delineated using a threshold-based semiautomatic delineation procedure for five brainstem structures. Regional BP (ND) values were estimated by applying the ROIs to the parametric images, and the percentage difference in BP (ND) between the systems was calculated.
Signals for [C-11]MADAM binding were obtained for all five brainstem structures. Overall, the HRRT provided 30-40 % higher BP (ND) values than the HR (p = 0.0017), independent of thresholds used in the ROI delineation procedure.
The methodology used enabled the estimation of [C-11]MADAM binding in the small nuclei of the brainstem. Differences in the BP (ND) values calculated using data from the two systems were mainly attributable to their differing resolutions. The estimated BP (ND) values provided lower across-subject variability than those previously obtained using compartment analysis. This procedure may therefore facilitate quantitative studies of receptor/transporter availability in the brainstem.

DOI： 10.1007/s00259-012-2260-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim The aim of this study was to investigate the influences of menopause on brain morphological changes in schizophrenia using magnetic resonance imaging (MRI). Methods Forty female schizophrenia patients, 20 premenopausal and 20 postmenopausal, and 50 female controls underwent cerebral MRI. Optimized voxel-based morphometry was performed with Statistical Parametric Mapping version 5. Results Compared with controls, regional gray matter reductions in schizophrenia patients were observed in the insula, superior temporal gyrus, anterior cingulate, parahippocampal gyrus, and thalamus. Direct comparison between the patient groups showed that the gray matter of postmenopausal patients was significantly smaller when compared with premenopausal patients in the left middle frontal gyrus, and no region had significantly lower gray matter volume in premenopausal patients relative to postmenopausal patients. Significant negative correlation between gray matter volume and the interval after menopause was found in the right superior frontal gyrus in the postmenopause patient group. Conclusion Differential morphological alterations between postmenopausal and premenopausal schizophrenia patients were observed, suggesting that the female hormone plays a protective role against schizophrenia. © 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.

DOI： 10.1111/pcn.12003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim The aim of this study was to investigate the influences of menopause on brain morphological changes in schizophrenia using magnetic resonance imaging (MRI). Methods Forty female schizophrenia patients, 20 premenopausal and 20 postmenopausal, and 50 female controls underwent cerebral MRI. Optimized voxel-based morphometry was performed with Statistical Parametric Mapping version 5. Results Compared with controls, regional gray matter reductions in schizophrenia patients were observed in the insula, superior temporal gyrus, anterior cingulate, parahippocampal gyrus, and thalamus. Direct comparison between the patient groups showed that the gray matter of postmenopausal patients was significantly smaller when compared with premenopausal patients in the left middle frontal gyrus, and no region had significantly lower gray matter volume in premenopausal patients relative to postmenopausal patients. Significant negative correlation between gray matter volume and the interval after menopause was found in the right superior frontal gyrus in the postmenopause patient group. Conclusion Differential morphological alterations between postmenopausal and premenopausal schizophrenia patients were observed, suggesting that the female hormone plays a protective role against schizophrenia.

DOI： 10.1111/pcn.12003

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記述言語：英語  

DOI： 10.1038/mp.2012.7

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記述言語：日本語   出版者・発行元：日本トラウマティック・ストレス学会 ; 2003-  

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その他リンク： http://search.jamas.or.jp/link/ui/2014089220

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記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0046488

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

UNLABELLED: (18)F-(E)-N-(3-iodoprop-2E-enyl)-2β-carbofluoroethoxy-3β-(4-methylphenyl)nortropane ((18)F-FE-PE2I) is a new PET radioligand with a high affinity and selectivity for the dopamine transporter (DAT). In nonhuman primates, (18)F-FE-PE2I showed faster kinetics and less production of radiometabolites that could potentially permeate the blood-brain barrier than did (11)C-PE2I. The aims of this study were to examine the quantification of DAT using (18)F-FE-PE2I and to assess the effect of radiometabolites of (18)F-FE-PE2I on the quantification in healthy humans. METHODS: A 90-min dynamic PET scan was obtained for 10 healthy men after intravenous injection of (18)F-FE-PE2I. Kinetic compartment model analysis with a metabolite-corrected arterial input function was performed. The effect of radiometabolites on the quantification was evaluated by time-stability analyses. The simplified reference tissue model (SRTM) method with the cerebellum as a reference region was evaluated as a noninvasive method of quantification. RESULTS: After the injection of (18)F-FE-PE2I, the whole-brain radioactivity showed a high peak (∼3-5 standardized uptake value) and fast washout. The radioactive uptake of (18)F-FE-PE2I in the brain was according to the relative density of the DAT (striatum > midbrain > thalamus). The cerebellum showed the lowest uptake. Tissue time-activity curves were well described by the 2-tissue-compartment model (TCM), as compared with the 1-TCM, for all subjects in all regions. Time stability analysis showed stable estimation of total distribution volume with 60-min or longer scan durations, indicating the small effect of radiometabolites. Binding potentials in the striatum and midbrain were well estimated by the SRTM method, with modest intersubject variability. Although the SRTM method yielded a slight underestimation and overestimation in regions with high and low DAT densities, respectively, binding potentials by the SRTM method were well correlated to the estimates by the indirect kinetic method with 2-TCM. CONCLUSION: (18)F-FE-PE2I is a promising PET radioligand for quantifying DAT. The binding potentials could be reliably estimated in both the striatum and midbrain using both the indirect kinetic and SRTM methods with a scan duration of 60 min. Although radiometabolites of (18)F-FE-PE2I in plasma possibly introduced some effects on the radioactivity in the brain, the effects on estimated binding potential were likely to be small.

DOI： 10.2967/jnumed.111.101626

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00213-011-2633-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NUCLEAR MEDICINE INC  

F-18-(E)-N-(3-iodoprop-2E-enyl)-2 beta-carbofluoroethoxy-3 beta-(4-methylphenyl)nortropane (F-18-FE-PE2I) is a new PET radioligand with a high affinity and selectivity for the dopamine transporter (DAT). In nonhuman primates, F-18-FE-PE2I showed faster kinetics and less production of radiometabolites that could potentially permeate the blood-brain barrier than did C-11-PE2I. The aims of this study were to examine the quantification of DAT using F-18-FE-PE2I and to assess the effect of radiometabolites of F-18-FE-PE2I on the quantification in healthy humans. Methods: A 90-min dynamic PET scan was obtained for 10 healthy men after intravenous injection of F-18-FE-PE2I. Kinetic compartment model analysis with a metabolite-corrected arterial input function was performed. The effect of radiometabolites on the quantification was evaluated by time-stability analyses. The simplified reference tissue model (SRTM) method with the cerebellum as a reference region was evaluated as a noninvasive method of quantification. Results: After the injection of F-18-FE-PE2I, the whole-brain radioactivity showed a high peak (similar to 3-5 standardized uptake value) and fast washout. The radioactive uptake of F-18-FE-PE2I in the brain was according to the relative density of the DAT (striatum &gt; midbrain &gt; thalamus). The cerebellum showed the lowest uptake. Tissue time-activity curves were well described by the 2-tissue-compartment model (TCM), as compared with the 1-TCM, for all subjects in all regions. Time stability analysis showed stable estimation of total distribution volume with 60-min or longer scan durations, indicating the small effect of radiometabolites. Binding potentials in the striatum and midbrain were well estimated by the SRTM method, with modest intersubject variability. Although the SRTM method yielded a slight underestimation and overestimation in regions with high and low DAT densities, respectively, binding potentials by the SRTM method were well correlated to the estimates by the indirect kinetic method with 2-TCM. Conclusion: F-18-FE-PE2I is a promising PET radioligand for quantifying DAT. The binding potentials could be reliably estimated in both the striatum and midbrain using both the indirect kinetic and SRTM methods with a scan duration of 60 min. Although radiometabolites of F-18-FE-PE2I in plasma possibly introduced some effects on the radioactivity in the brain, the effects on estimated binding potential were likely to be small.

DOI： 10.2967/jnumed.111.101626

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D₂ receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D₂ receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D₂ receptors have reported inconsistent results regarding regional differences of dopamine D₂ receptor occupancy by aripiprazole.To test the hypothesis of preferential binding to extrastriatal dopamine D₂ receptors by aripiprazole, we investigated its regional dopamine D₂ receptor occupancies in healthy young subjects.Using PET and two radioligands with different affinities for dopamine D₂ receptors, [¹¹C]raclopride and [¹¹C]FLB457, striatal and extrastriatal dopamine D₂ receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy

DOI： 10.1007/s00213-011-2633-5

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記述言語：日本語   出版者・発行元：(公財)臨床薬理研究振興財団  

臨床で使用されているsulpirideを標識した[11C]sulpirideを開発し、まずサルを用いて基礎的な検討を行った後、ヒト(健常成人2名)を対象に、[11C]sulpirideの全身分布・脳移行性・脳内動態をPETで観察し、さらに臨床用量sulpiride内服後の変化について検討した。結果、サル・ヒトともsulpirideの脳への移行性は低いことが示唆された。臨床用量を内服した場合には、比較的多量のsulpirideが全身(脳外)に曝露されることにより、そのごく一部が脳へ移行し向精神薬としての作用を発現することが推測された。

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness.

DOI： 10.1073/pnas.1118687109

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/syn.20883

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記述言語：日本語   出版者・発行元：(一社)日本核医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NEUROSCIENCE  

Both presynaptic and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET). While both presynaptic and postsynaptic dopaminergic functions would be regulated by corresponding genes and related to personality traits, the relation between presynaptic and postsynaptic functions in terms of interindividual variation has hardly been investigated. In the present study, both striatal dopamine D(2) receptor binding and endogenous dopamine synthesis rate were measured in the same healthy subjects using PET with [(11)C]raclopride and L-[beta-(11)C]DOPA, respectively, and these two parameters were compared. Two PET studies with [(11)C] raclopride and L-[beta-(11)C] DOPA were performed sequentially at rest condition on 14 healthy men. For [(11)C] raclopride PET, the binding potential was calculated by the reference tissue model method. For L-[beta-(11)C]DOPAPET, the endogenous dopamine synthesis rate was estimated by graphical analysis. A significant negative correlation was observed between the binding potential of dopamine D(2) receptors and endogenous dopamine synthesis rate (r = -0.66, p &lt; 0.05). Although the interindividual variation of binding potential of [(11)C] raclopride would be due to both the interindividual difference in the receptor density and that in the concentration of endogenous dopamine in the synaptic cleft, the negative correlation between parameters for both presynaptic and postsynaptic functions might indicate a compensative relation between the two functions.

DOI： 10.1523/JNEUROSCI.6024-10.2011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In conventional pharmacological research in the field of mental disorders, pharmacological effect and dose have been estimated by ethological approach and in vitro data of affinity to the site of action. In addition, the frequency of administration has been estimated from drug kinetics in blood. However, there is a problem regarding an objective index of drug effects in the living body. Furthermore, the possibility that the concentration of drug in blood does not necessarily reflect the drug kinetics in target organs has been pointed out. Positron emission tomography (PET) techniques have made progress for more than 20 years, and made it possible to measure the distribution and kinetics of small molecule components in living brain. In this article, we focused on rational drug dosing using receptor occupancy and proof-of-concept of drugs in the drug development process using PET.

DOI： 10.9758/cpn.2011.9.1.9

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：(一社)日本核医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CAMBRIDGE UNIV PRESS  

The increased proportion of the high-affinity state of dopamine D-2/3 receptors (D-2,D-high) is assumed to correlate with dopamine hypersensitivity, implying a relationship with psychotic symptoms observed in psychiatric disorders such as schizophrenia. [C-11](R)-2-CH3O-N-n-propylnorapomorphine ([C-11]MNPA), which has an agonistic property to dopamine D-2 receptors (D(2)Rs), is expected to bind preferentially to D-2,D-high. The occupancy of dopamine D(2)Rs by antagonists to receptors has not been investigated using [C-11]MNPA. We compared dopamine D2R occupancies by risperidone, an antagonist to receptors, between [C-11]MNPA and [C-11]raclopride to confirm whether risperidone occupies D-2,D-high and D-2,D-low at almost identical proportions. PET studies were performed on 11 healthy men under resting condition and following oral administration of a single dose of risperidone (0.5-2.0 mg). Striatal receptor occupancy for each radioligand was calculated. The relationship between dose or plasma concentration of risperidone and dopamine D2R occupancy was calculated. Striatal dopamine D2R occupancies measured with [C-11]MNPA and [C-11]raclopride were 22-65% and 24-69%, respectively. In the striatum, ED50 values measured with [C-11]MNPA and [C-11]raclopride were 0.98 and 1.03 mg, respectively. The striatal ED50 values as calculated from plasma concentration were 9.15 ng/ml and 8.01 ng/ml, respectively. Almost identical occupancies and ED50 values were observed between the two radioligands, indicating that risperidone bound to D-2,D-high and D-2,D-low at almost identical proportions in a dose-dependent manner.

DOI： 10.1017/S1461145710001148

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1523/JNEUROSCI.3933-10.2010

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12149-010-0407-5

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記述言語：日本語   出版者・発行元：(一社)日本核医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4088/JCP.08m04307yel

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記述言語：英語   出版者・発行元：(一社)日本核医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CAMBRIDGE UNIV PRESS  

Inflammatory/immunological process and glial contribution are suggested in the pathophysiology of schizophrenia. We investigated peripheral benzodiazepine receptors in brains of patients with chronic schizophrenia, which were reported to be located on mitochondria of glial cells, using [C-11]DAA1106 with positron emission tomography. Fourteen patients and 14 age- and sex-matched normal controls participated in this study. PET data were analysed by two-tissue compartment model with metabolite-corrected plasma input. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale. There was no significant difference between [C-11]DAA1106 binding of the cortical regions of normal controls and patients with schizophrenia, whereas the patients showed a positive correlation between cortical [C-11]DAA1106 binding and positive symptom scores. There was also a positive correlation between [C-11]DAA1106 binding and duration of illness. Although the correlations need to be interpreted very cautiously, involvement of glial reaction process in the pathophysiology of positive symptoms or progressive change of schizophrenia might be suggested.

DOI： 10.1017/S1461145710000313

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CAMBRIDGE UNIV PRESS  

In our previous positron emission tomography (PET) study, we demonstrated that ECT decreased dopamine D, receptor in major depressive disorder (MDD). Although many animal studies have focused on the effect of ECT on serotonergic neurotransmission, no human study has directly examined the effect of ECT on brain serotonin [5-hydroxytryptamine (5-HT)] 1A receptors (5-HT(1A)Rs). Using PET with [C-11]WAY 100635, we aimed to evaluate the effect of ECT on 5-HT(1A)Rs in patients with MDD. Nine patients underwent PET scans before and after a series of 6-7 bilateral ECTs. Region-of-interest analysis was performed based on the simplified reference tissue model. There were no significant changes in 5-HT1AR binding in patients between before and after ECT. ECT did not alter [C-11]WAY 100635 binding even after recovery from depressive episode. Although the present finding does not exclude the involvement of brain 5-HT1A systems in the antidepressant action of ECT, it may indicate the involvement of other neurotransmission mechanisms.

DOI： 10.1017/S1461145709991209

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI LTD  

Background: Microglial activation and disrupted neurotransmissions may herald symptomatic manifestations in neurodegenerative tauopathies.
Methods: We investigated microglial activation with [(11)C]DAA1106 positron emission tomography (PET), striatal dopaminergic function with L-[beta-(11)C]dopa PET, acetylcholinesterase (AChE) activity with [(11)C]N-methylpiperidin-4-yl acetate PET, and morphologic brain changes with MRI in three persons (aged 38-41 years) with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), who were presymptomatic gene carriers (PGCs) from an American kindred with pallidopontonigral degeneration. The results from these 3 PGCs were compared with [(11)C]DAA1106 PET results from age-matched 9 healthy volunteers (HV), and with L-[beta-(11)C]dopa and [(11)C]MP4A PET results from 10 HV. Values considered significant were more than 2 SDs greater or less than the normal control mean, as the number of subjects was small for group comparisons.
Results: Glial activities were increased in the frontal cortex of one PGC, the occipital cortex of two PGCs, and the posterior cingulate cortex of one PGC, although none of the PGCs showed overt glial activation in the brain. Only one of the PGCs showed reduced AChE activity in the temporo-parietal cortex. Three PGCs showed low dopamine synthesis rates in the putamen. Hippocampal atrophy was observed in two PGCs.
Conclusions: Hippocampal atrophy and striatal dopaminergic dysfunction may be early disease processes in the pathogenesis of FTDP-17. Neuroinflammation may also be an in vivo signature of tau pathology at a prodromal stage, although current PET techniques may not constantly reveal it as the earliest neuroimaging abnormality. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.parkreldis.2010.04.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Central norepinephrine transporter (NET) is one of the main targets of antidepressants. Although the measurement of NET occupancy has been attempted in humans, the outcomes have been inconclusive.
In this study, the occupancy of NET by different doses of an antidepressant, nortriptyline, was measured using positron emission tomography (PET) with (S,S)-[F-18]FMeNER-D-2.
PET scans using (S,S)-[F-18]FMeNER-D-2 were performed on six healthy men before and after oral administration of a single oral dose of nortriptyline (10-75 mg). After a bolus i.v. injection of (S,S)-[F-18]FMeNER-D-2, dynamic scanning was performed for 0-90 min, followed by scanning for 120-180 min. The ratio of the thalamus-to-caudate areas under the curve (120-180 min) minus 1 was used as the binding potential (BPND) for NET. NET occupancy was calculated as the percentage reduction of BPND. Venous blood samples were taken to measure the concentrations of nortriptyline just before injection of the tracer and at 180 min after the injection.
Mean NET occupancies by nortriptyline were 16.4% at 10 mg, 33.2% at 25 mg, and 41.1% at 75 mg. The mean plasma concentration of nortriptyline was less than the lower limit of detection at 10 mg, 23.7 ng/mL at 25 mg, and 50.5 ng/mL at 75 mg. Estimated ED50 was 76.8 mg of administration dose and 59.8 ng/mL of plasma concentration.
NET occupancy by nortriptyline corresponding to the administration dose of 10-75 mg or plasma concentration was observed from 16% to 41%.

DOI： 10.1007/s00213-010-1824-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4088/JCP.08m04746blu

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER HEIDELBERG  

Olanzapine is described as a multi-acting receptor-targeted antipsychotic agent. Although regional differences of dopamine D-2 receptor occupancy, i.e., limbic selectivity, were reported for olanzapine, contradictory results were also reported. We measured dopamine D-2 receptor occupancy of olanzapine in extrastriatal regions in patients with schizophrenia using positron-emission tomography with [C-11]FLB457 and the plasma concentrations of olanzapine. Ten patients with schizophrenia taking 5-20 mg/day of olanzapine participated. Dopamine D-2 receptor occupancy in the temporal cortex ranged from 61.1 to 85.8%, and plasma concentration was from 12.7 to 115.4 ng/ml. The ED50 value was 3.4 mg/day for dose and 10.5 ng/ml for plasma concentration. The ED50 values obtained in this study were quite similar to those previously reported in the striatum. In conclusion, although the subjects and methods were different from previous striatal occupancy studies, these results suggest that limbic occupancy by olanzapine may not be so different from that in the striatum.

DOI： 10.1007/s00406-009-0082-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Dopamine transporter (DAT) is a reuptake carrier of dopamine at presynapse that regulates dopaminergic neural transmission. [C-11]PE2I is a cocaine analog developed as a potent positron emission tomography (PET) ligand for DAT with high selectivity. The aim of this study was to evaluate the applicability of quantification methods using reference tissue models for [C-11]PE2I.
Dynamic PET scans were performed in 6 young healthy male volunteers after an intravenous bolus injection of [C-11]PE2I. Metabolite-corrected arterial plasma-input functions were obtained. Compartment model analysis and plasma-input Logan analysis were performed to determine the kinetic parameters and distribution volume (V (T)). The distribution volume ratio (DVR) was calculated as the ratio of V (T) in the cerebral region to that in the cerebellum. DVRs were also determined by the original multilinear reference tissue model method (MRTMo) and the simplified reference tissue model method (SRTM), comparing the results with those obtained from graphical analysis using arterial input function. To estimate errors in DVR calculated using the reference tissue model, a simulation study that focused on cerebellar kinetics and scan duration was performed.
The highest [C-11]PE2I binding was observed in the striatum, followed by the midbrain and thalamus. The 2-tissue model was preferable to the 1-tissue model for describing the [C-11]PE2I kinetics in the cerebellum. Both the measured and 90-min simulated data showed that reference tissue models caused an underestimation of DVR in the striatum. The simulation showed that 90-min scan duration was insufficient when cerebellar kinetics was described as a 1-tissue model. Nevertheless, DVR values determined by MRTMo and SRTM were in good agreement with those by the graphical approach in other lower binding regions.
Due to the [C-11]PE2I kinetics in the cerebellum and limited scan duration for C-11, MRTMo and SRTM underestimated the striatal DVR. Despite this limitation, the present study demonstrated the applicability of reference tissue models. Since DAT in the midbrain and thalamus is of interest in the pathophysiology of neuropsychiatric disease, this noninvasive quantitative analysis will be useful for clinical investigations.

DOI： 10.1007/s12149-010-0364-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Perospirone is a novel second-generation antipsychotic drug with high affinity to dopamine D-2 receptor and short half-life of plasma concentration. There has been no investigation of dopamine D-2 receptor occupancy in patients with schizophrenia and the time course of occupancy by antipsychotics with perospirone-like properties.
We investigated dopamine D-2 receptor occupancy by perospirone in patients with schizophrenia and the time course of occupancy in healthy subjects.
Six patients with schizophrenia taking 16-48 mg/day of perospirone participated. Positron emission tomography (PET) scans using [C-11]FLB457 were performed on each subject, and dopamine D-2 receptor occupancies were calculated. Moreover, baseline and three serial PET using [C-11]raclopride were performed at 1.5, 8, and 25.5 h after administration of a single dose of 16 mg of perospirone on four healthy male subjects, and occupancy was calculated for each scan.
Dopamine D-2 receptor occupancy in the temporal cortex of patients ranged from 39.6% to 83.8%. Especially, occupancy in two patients who took 16 mg of perospirone 2.5 h before PET was over 70%. Mean occupancy in the striatum of healthy subjects was 74.8% at 1.5 h, 60.1% at 8 h, and 31.9% at 25.5 h after administration.
Sixteen milligrams of perospirone caused over 70% dopamine D-2 receptor occupancy near its peak level, and then occupancy dropped to about half after 22 h. The time courses of receptor occupancy and plasma concentration were quite different. This single dosage may be sufficient for the treatment of schizophrenia and might be useful as a new dosing schedule choice.

DOI： 10.1007/s00213-010-1783-1

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記述言語：日本語  

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記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12149-009-0336-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NEUROSCIENCE  

Several animal studies have demonstrated functional roles of dopamine (DA) D1 and D2 receptors in amygdala activity. However, the contribution of DA D1 and D2 receptors to amygdala response induced by affective stimuli in human is unknown. To investigate the contribution of DA receptor subtypes to amygdala reactivity in human, we conducted a multimodal in vivo neuroimaging study in which DA D1 and D2 receptor bindings in the amygdala were measured with positron emission tomography (PET), and amygdala response induced by fearful faces was assessed by functional magnetic resonance imaging (fMRI) in healthy volunteers. We used multimodality voxelwise correlation analysis between fMRI signal and DA receptor binding measured by PET. DA D1 binding in the amygdala was positively correlated with amygdala signal change in response to fearful faces, but DA D2 binding in the amygdala was not related to amygdala signal change. DA D1 receptors might play a major role in enhancing amygdala response when sensory inputs are affective.

DOI： 10.1523/JNEUROSCI.5689-09.2010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

The purpose of this study is to investigate errors in quantitative analysis for estimating dopamine D-2 receptor occupancy of antipsychotics with agonist radioligand [C-11]MNPA by numerical simulation, with particular attention to the validity of a quantitative approach based on the use of a reference region. Synthetic data were validated using clinical data combined with a bootstrap approach. Time-activity curves (TACs) of [C-11]MNPA were simulated, and the reliability of binding potential (BPND) and occupancy estimated by nonlinear least square (NLS) fitting and a simplified reference tissue model (SRTM) were investigated for various noise levels and scan durations. In the human positron emission tomography (PET) study with and without antipsychotic, risperidone, the uncertainty of BPND and occupancy estimated by SRTM was investigated using resampled TACs based on bootstrap approach with weighted residual errors of fitting. For both NLS and SRTM, it was possible to have &lt; 3% of bias in occupancy estimates of [C-11]MNPA by 60 mins. However, shortened scan duration degrades the quantification of very small binding potentials, especially in case of SRTM. Observations were replicated on the clinical data. Results showed that dopamine D-2 receptor occupancy by antipsychotics can be estimated precisely in region of interest analysis by SRTM with a longer than 60-min [C-11]MNPA PET scan duration. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 187-195; doi: 10.1038/jcbfm.2009.193; published online 16 September 2009

DOI： 10.1038/jcbfm.2009.193

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The serotonin transporter (5-HTT) and other markets of the serotonergic system have been of interest in the pathophysiology of obsessive-compulsive disorder (OCD). Previous studies using single photon emission computed tomography (SPECT) with [I-123]beta-CIT or positron emission tomography (PET) with [C-11]McN5652 have not shown consistent findings about 5-HTT in OCD patients. The aim of the present study was to investigate 5-HTT binding using [C-11]DASB, which has higher selectivity or specific binding-to-nonspecific binding ratios for 5-HTT compared to the aforementioned radioligands. Four drug-naive and 6 drug-free patients with OCD who were free of comorbid depression and 18 gender and age-matched healthy subjects underwent PET scans with [C-11]DASB. The severity of OCD was assessed by Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (mean +/- SD: 22 +/- 7.6, range: 7-32). The binding potential (BPND) of [C-11]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2). The parametric images of BPND were analyzed using a statistical parametric mapping system. Significant reductions of BPND were observed in the right posterior and left anterior insular cortices in patients with OCD compared to controls. Region-of-interest analysis has also confirmed significant reduction of BPND in the insular cortex. Although significantly reduced BPND in the orbitolfrontal cortex was also observed in patients with OCD compared to controls, this finding should be considered with caution because of the very low 5-HTT binding in the region. On the other hand, no significant correlation was observed between the Y-BOCS score and BPND. The change in [C-11]DASB binding in the insular cortex suggests that dysfunction of the serotonergic system in the limbic area might be involved in the pathophysiology of OCD. (c) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neuroimage.2009.07.069

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：寺田国際事務所先端医療技術研究所  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim:
Somatoform pain disorder is characterized by persistent and chronic pain at one or more sites without an associated general medical condition and in which psychological factors are thought to play a role. This study aimed to investigate the pathological features of somatoform pain disorder localized to the oral region by single photon emission computed tomography (SPECT).
Methods:
Ten patients (nine females and one male; average age 55.0 +/- 14.4 years) having somatoform pain disorder with oral symptoms participated. SPECT was performed using N-isopropyl-4-[123I] iodoamphetamine intravenous injections, and regional cerebral blood flow (rCBF) was assessed by three-dimensional stereotactic surface projections. We also selected 12 healthy individuals (seven females and five males; average age 61.8 +/- 13.2 years) to act as controls.
Results:
Both the patient and control groups showed no atrophy or infarction on CT or magnetic resonance imaging. The patient group showed higher rCBF in the subcortical area, especially in the thalamus and cingulate gyri, than the control group. In contrast, the patient group showed lower rCBF in the bilateral frontal and occipital lobes as well as in the left temporal lobe.
Conclusions:
These results suggest that the biological process involved in somatoform pain disorder of the oral region is characterized by changes in limbic and cortical functions. The finding that somatoform pain disorder with oral symptoms is associated with brain functional changes will help to develop treatment regimes for this disorder and clarify the underlying pathology.

DOI： 10.1111/j.1440-1819.2010.02119.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NEUROSCIENCE  

Effects of antipsychotic drugs have widely been considered to be mediated by blockade of postsynaptic dopamine D-2 receptors. Effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission might also be related to therapeutic effects of antipsychotics. To investigate the effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission in relation with occupancy of dopamine D-2 receptors, changes in dopamine synthesis capacity by antipsychotics and occupancy of dopamine D-2 receptors were measured by positron emission tomography (PET) in healthy men. PET studies using [C-11] raclopride and L-[beta-C-11] DOPA were performed under resting condition and oral administration of single dose of the antipsychotic drug risperidone on separate days. Although occupancy of dopamine D-2 receptors corresponding dose of risperidone was observed, the changes in dopamine synthesis capacity by the administration of risperidone were not significant, nor was the relation between the occupancy of dopamine D-2 receptors and these changes. A significant negative correlation was observed between the baseline dopamine synthesis capacity and the changes in dopamine synthesis capacity by risperidone, indicating that this antipsychotic can be assumed to stabilize the dopamine synthesis capacity. The therapeutic effects of risperidone in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.

DOI： 10.1523/JNEUROSCI.4172-09.2009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Previous in vivo imaging studies reported no difference in dopamine transporter (DAT) bindings in the striatum between control subjects and patients with schizophrenia. However, as the signals of radioligands with moderate affinity were insufficient for allowing the evaluation of small amounts of DAT, DAT binding in extrastriatal regions has not been determined. Positron emission tomography scanning using [C-11]PE2I was performed on eight patients with schizophrenia and twelve normal control subjects. Binding potential (BPND) for DAT in the caudate, putamen, thalamus and substantia nigra was calculated, using the cerebellum as reference region. In patients with schizophrenia, clinical symptoms were evaluated by Positive and Negative Syndrome Scale (PANSS). BPND in the thalamus of patients with schizophrenia was significantly higher than in control subjects (P = 0.044). In patients with schizophrenia, there were significantly positive correlations between BPND in the thalamus and total (r = 0.75), positive (r = 0.78) and negative PANSS scores (r = 0.82). Altered DAT in the thalamus might be related to the pathophysiology and clinical symptoms of schizophrenia. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jpsychires.2009.04.009

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記述言語：日本語   出版者・発行元：(一社)日本核医学会  

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記述言語：日本語   出版者・発行元：(一社)日本核医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NUCLEAR MEDICINE INC  

Peripheral benzodiazepine receptor (PBR) is upregulated in activated glial cells and is therefore a useful biomarker for inflammation in the brain and neurodegenerative disorders. We developed a new PET radioligand, (11)C-AC-N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-pheyl-7,8-dihydro-9H-purin-9-yl)acetamide ((11)C-AC-5216), that allows the imaging and quantification of PBRs in monkey and mouse brains. The aim of this study was to evaluate a quantification method of (11)C-AC-5216 binding in the human brain. Methods: A 90-min dynamic PET scan was obtained for each of 12 healthy men after an intravenous injection of (11)C-AC-5216. Regions of interest were drawn on several brain regions. Binding potential, compared with nondisplaceable uptake (BP(ND)), was calculated by a nonlinear least-squares fitting (NLS) method with the 2-tissue-compartment model, and total volume of distribution (V(T)) was estimated by NLS and graphical analysis methods. Results: BPND was highest in the thalamus (4.6 +/- 1.0) and lowest in the striatum (3.5 +/- 0.7). V(T) obtained by NLS or graphical analysis showed regional distribution similar to BPND. However, there was no correlation between BPND and VT because of the interindividual variation of K(1)/k(2). BPND obtained with data from a scan time of 60 min was in good agreement with that from a scan time of 90 min (r = 0.87). Conclusion: Regional distribution of (11)C-AC-5216 was in good agreement with previous PET studies of PBRs in the human brain. BP(ND) is more appropriate for estimating (11)C-AC-5216 binding than is VT because of the interindividual variation of K(1)/k(2). (11)C-AC-5216 is a promising PET ligand for quantifying PBR in the human brain.

DOI： 10.2967/jnumed.109.062554

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CAMBRIDGE UNIV PRESS  

The effects of antipsychotic drugs have generally been considered to be mediated by blockade of dopamine D-2 receptors. The concept of limbic and cortical selectivity of second-generation antipsychotics, i.e. higher dopamine D-2 receptor occupancy in the cerebral cortices than in the striatum, has been Suggested to explain their clinical efficacy with lower incidence of extrapyramidal side-effects. In this study, regional distribution of dopamine D-2 receptor occupancy by risperidone was determined in order to elucidate the limbic and cortical selectivity of second-generation antipsychotics. Striatal and extrastriatal dopamine D-2 receptor binding at baseline and after oral administration of 2 mg risperidone were measured in ten healthy men by positron emission tomography (PET) using different tracers with different affinity for the receptors, [C-11]raclopride and [C-11]FLB 457, respectively. Striatal and extrastriatal occupancies of dopamine D-2 receptors were calculated for each brain region. Occupancies of dopamine D-2 receptors were about 70%, and 60% in the striatum and extrastriatum, respectively. A simulation study showed that non-negligible specific binding in the reference region (cerebellum), could cause systemic underestimation of occupancy in [C-11]FLB 457 PET studies, indicating that occupancies in both the striatum and extrastriatum may not have differed. Among the extrastriatal regions including limbic and neocortical regions, no significant regional differences in dopamine D receptor occupancy were observed. Thus, limbic and cortical selectivity was not observed by one of the second-generation antipsychotics, risperidone.

DOI： 10.1017/S1461145708009577

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NUCLEAR MEDICINE INC  

It has been demonstrated in vitro that the dopamine D-2 receptor has 2 interconvertible affinity states for endogenous dopamine, referred to as the high-and the low-affinity states. C-11-(R)-2-CH3O- N-n-propylnorapomorphine (C-11-MNPA) is a new agonist radioligand for in vivo imaging of the high-affinity state of dopamine D-2 receptors using PET. In the present study, the kinetics of C-11-MNPA were examined for the first time, to our knowledge, in the human brain and analyzed using quantitative approaches with or without an arterial input function. Methods: A 90-min dynamic PET scan was obtained for 10 healthy men after an intravenous injection of C-11-MNPA. The binding potential (BPND) was calculated using the indirect kinetic method, a kinetic compartment analysis with a metabolite-corrected arterial input function. BPND was also calculated by the simplified reference tissue model (SRTM) and transient equilibrium methods, both with the cerebellum as the reference brain region. The results of the quantitative methods were compared in a cross-validation approach. Results: The highest regional radioactivity was observed in the putamen. BPND values obtained by kinetic analysis were 0.82 +/- 0.09, 0.59 +/- 0.11, and 0.28 +/- 0.06, respectively, in the putamen, caudate, and thalamus. BPND values obtained by the SRTM and transient equilibrium methods were in good agreement with those obtained by the indirect kinetic method (r = 0.98 and r - 0.93, respectively). For all quantification methods, the BPND values based on data acquired from 0 to 60 min were in good agreement with those based on data acquired from 0 to 90 min (r = 0.90-0.99). Conclusion: The regional distribution of C-11-MNPA binding was in good agreement with previous PET studies of dopamine D-2 receptors in the human brain using antagonist radioligands. The results support routine use of the SRTM and transient equilibrium methods, that is, methods that do not require an arterial input function and need a scan time of only about 60 min. C-11-MNPA should thus be useful for clinical research on the pathophysiology of neuropsychiatric disorders and estimation of dopamine D-2 receptor occupancy by dopaminergic drugs.

DOI： 10.2967/jnumed.108.058503

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

The dopamine hypothesis has been the most widely known theory concerning schizophrenia. However, the exact mechanism including presynaptic dopaminergic activity and its relationship with symptom severity still remains to be revealed. We measured presynaptic dopamine synthesis using positron emission tomography (PET) with L-[beta-C-11]DOPA in 18 patients with schizophrenia (14 drug-naive and 4 drug-free patients) and 20 control participants. Dopamine synthesis rates, expressed as k(i) values, were obtained using a graphical method, and the occipital cortex was used as reference region. Regions of interest were placed on the prefrontal cortex, temporal cortex, anterior cingulate, parahippocampus, thalamus, caudate nucleus, and putamen. Psychopathology was assessed with the Positive and Negative Symptom Scale (PANSS). We found significantly higher ki values in patients than in controls in the left caudate nucleus, but not in the other regions. The ki values in the thalamus exhibited a significant positive correlation with the PANSS total scores. Furthermore, a significant positive correlation was observed between the PANSS positive subscale scores and ki values in the right temporal cortex. Patients with schizophrenia showed higher dopamine synthesis in the left caudate nucleus, and dopaminergic transmission in the thalamus and right temporal cortex might be implicated in the expression of symptoms in schizophrenia. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2008.11.006

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記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NEUROSCIENCE  

Dopamine D-1 receptors in the prefrontal cortex (PFC) are important for prefrontal functions, and it is suggested that stimulation of prefrontal D-1 receptors induces an inverted U-shaped response, such that too little or too much D-1 receptor stimulation impairs prefrontal functions. Less is known of the role of D-2 receptors in cognition, but previous studies showed that D-2 receptors in the hippocampus (HPC) might play some roles via HPC-PFC interactions. We measured both D-1 and D-2 receptors in PFC and HPC using positron emission tomography in healthy subjects, with the aim of elucidating how regional D-1 and D-2 receptors are differentially involved in frontal lobe functions and memory. We found an inverted U-shaped relation between prefrontal D-1 receptor binding and Wisconsin Card Sorting Test performance. However, prefrontal D-2 binding has no relation with any neuropsychological measures. Hippocampal D-2 receptor binding showed positive linear correlations not only with memory function but also with frontal lobe functions, but hippocampal D-1 receptor binding had no association with any memory and prefrontal functions. Hippocampal D-2 receptors seem to contribute to local hippocampal functions (long-term memory) and to modulation of brain functions outside HPC ("frontal lobe functions"), which are mainly subserved by PFC, via the HPC-PFC pathway. Our findings suggest that orchestration of prefrontal D-1 receptors and hippocampal D-2 receptors might be necessary for human executive function including working memory.

DOI： 10.1523/JNEUROSCI.3446-08.2008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NUCLEAR MEDICINE INC  

F-18-fluoroethyl-SPA-RQ (F-18-FE-SPA-RQ) was recently developed as a radioligand for the measurement of neurokinin 1 (NK1) receptor with PET. In this study, we used F-18-FE-SPA-RQ with PET to visualize and quantify NK1 receptor in the human brain. Methods: PET scans were performed on 7 healthy men after intravenous injection of F-18-FE-SPA-RQ. Binding potential (BPNp) was calculated by the indirect kinetic, simplified reference tissue model (SRTM), and ratio methods. The indirect kinetic method was used as the gold standard method and was compared with the SRTM method, with scan times of 180, 270, and 330 min, and with the ratio method, with time integration intervals of 120-180, 210-270, and 300-330 min. The cerebellum was used as the reference brain region. Results: Regional radioactivity was highest in the caudate head and putamen; mid level in the parahippocampus, cerebral cortex, and thalamus; and lowest in the cerebellum. BPND values by the indirect kinetic method were 3.15 +/- 0.36, 3.11 +/- 0.66, 1.17 +/- 0.25, and 0.46 +/- 0.14 in the caudate, putamen, parahippocampal region, and thalamus, respectively. For cerebral cortical regions, BPNp values by the indirect kinetic method were 0.94 +/- 0.23, 0.82 +/- 0.15, 0.76 +/- 0.15, and 0.69 +/- 0.16 in the occipital, temporal, frontal, and anterior cingulate cortices, respectively. BPNp values by the SRTM and ratio methods were in good agreement with those by the indirect kinetic method (r = 0.94-0.98). Conclusion: The regional distribution of F-18-FE-SPA-RQ was in agreement with previous PET studies and postmortem studies of NK1 receptor in the human brain. The ratio method will be useful for clinical research of psychiatric disorders, for the estimation of NK1 receptor without arterial blood sampling and long dynamic PET.

DOI： 10.2967/jnumed.108.054353

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Dopamine D(2) receptor occupancy by antipsychotic drugs has been measured with positron emission tomography (PET) by comparing the binding potential (BP) values before and after drug administration. This occupancy has been found to be related to clinical effects and side effects. in this study, we evaluated the in simulation and human studies of [(11)C]raclopride and for the high affinity ligand [(11)C]FLB 457. Time-activity curves of [(11)C]raclopride and [(11)C]FLB 457 were simulated, and the reliability of BP estimated by a simplified reference tissue model and the calculated Occupancy were investigated for various noise levels, BP values, and scan durations. Then, in the human PET study with and without antipsychotics, the uncertainty of BP and occupancy estimates and the scan duration required for a reliable estimation were investigated by a bootstrap approach. Reliable and unbiased estimates of [(11)C]raclopride BP(ND) could be obtained with recording as short as 32 min, with the relative standard deviation (SD) of the striatal occupancy remaining less than 10%. Conversely, in [(11)C]FLB 457 Studies, the mean value increased and SD of the temporal cortex and thalamus exceeded 10% when the scan duration was shorter than 60 min. These results demonstrated that dopamine D(2) receptor occupancy by antipsychotics can be estimated precisely with an optimal scan duration with [(11)C]raclopride and [(11)C]FLB 457. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neuroimage.2008.05.056

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記述言語：日本語   出版者・発行元：(一社)日本核医学会  

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記述言語：日本語   出版者・発行元：(一社)日本核医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NUCLEAR MEDICINE INC  

(S,S)-F-18-FMeNER-D-2 was recently developed as a radioligand for the measurement of norepinephrine transporter imaging with PET. In this study, a norepinephrine transporter was visualized in the human brain using this radioligand with PET and quantified by several methods. Methods: PET scans were performed on 10 healthy men after intravenous injection of (S,S)-(FFMeNER)-F-18-D-2. Binding potential relative to nondisplaceable binding (BPND) was quantified by the indirect kinetic, simplified reference-tissue model (SRTM), multilinear reference-tissue model (MRTM), and ratio methods. The indirect kinetic method was used as the gold standard and was compared with the SRTM method with scan times of 240 and 180 min, the MRTM method with a scan time of 240 min, and the ratio method with a time integration interval of 120-180 min. The caudate was used as reference brain region. Results: Regional radioactivity was highest in the thalamus and lowest in the caudate during PET scanning. BPND values by the indirect kinetic method were 0.54 +/- 0.19 and 0.35 +/- 0.25 in the thalamus and locus coeruleus, respectively. BPND values found by the SRTM, MRTM, and ratio methods agreed with the values demonstrated by the indirect kinetic method (r = 0.81-0.92). Conclusion: The regional distribution of (S,S)-F-18-FMeNER-D-2 in our study agreed with that demonstrated by previous PET and postmortem studies of norepinephrine transporter in the human brain. The ratio method with a time integration interval of 120-180 min will be useful for clinical research of psychiatric disorders for estimation of norepinephrine transporter occupancy by antidepressants without requiring arterial blood sampling and dynamic PET.

DOI： 10.2967/jnumed.108.051292

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Rationale Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects.
Objectives In this study, we measured striatal and extrastriatal dopamine D(2) receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose.
Materials and methods Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [(11)C]raclopride and one with [(11)C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D(2) receptor occupancy was calculated.
Results The dopamine D(2) receptor occupancies in the striatum measured with [(11)C]raclopride and the temporal cortex measured with [(11)C]FLB 457 were 54.2-85.5% and 34.5-87.3%, respectively. ED(50) values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D(2) receptor occupancy between the striatum and the temporal cortex.
Conclusions The data from this study suggest that paliperidone ER at 6-9 mg provides an estimated level of dopamine D(2) receptor occupancy between 70-80% and that the magnitude of dopamine D(2) receptor occupancy is similar between the striatum and temporal cortex.

DOI： 10.1007/s00213-007-1029-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Dysfunction of the GABA system is considered to play a role in the pathology of schizophrenia. Individual subunits of GABA(A)/Benzodiazepine (BZ) receptor complex have been revealed to have different functional properties. alpha 5 subunit was reported to be related to learning and memory. Changes of a5 subunit in schizophrenia were reported in postmortem studies, but the results were inconsistent. In this study, we examined GABA(A)/BZ receptor using [C-11]Rol5-4513, which has relatively high affinity for (alpha 5 subunit, and its relation to clinical symptoms in patients with schizophrenia. [C-11]Rol5-4513 bindings of I I patients with schizophrenia (6 drug-naive and 5 drug-free) were compared with those of 12 age-matched healthy control subjects using positron emission tomography. Symptoms were assessed using the Positive and Negative Syndrome Scale. [C-11]Rol5-4513 binding was quantified by binding potential (BP) obtained by the reference tissue model. [C-11] Ro15-4513 binding in the prefrontal cortex and hippocampus was negatively correlated with negative symptom scores in patients with schizophrenia, although there was no significant difference in BP between patients and controls. GABAA/BZ receptor including alpha 5 subunit in the prefrontal cortex and hippocampus might be involved in the pathophysiology of negative symptoms of schizophrenia. (C) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2007.10.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The central dopaminergic system is of interest in the pathophysiology of schizophrenia and other neuropsychiatric disorders. Both pre- and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET) with different radiotracers. However, an integrated database of both pre- and postsynaptic dopaminergic neurotransmission components including receptors, transporter, and endogenous neurotransmitter synthesis has not yet been reported. In the present study, we constructed a normal database for the pre- and postsynaptic dopaminergic functions in the living human brain using PET. To measure striatal and extrastriatal dopamine D-1 and D-2 receptor bindings, dopamine transporter binding, and endogenous dopamine synthesis rate, PET scans were performed on healthy men after intravenous injection of [C-11]SCH23390, [C-11]raclopride, [C-11]FLB457, [C-11]PE21, or L-[beta-C-11]DOPA. All PET images were anatomically standardized using SPM2, and a database was built for each radiotracer. Gray matter images were segmented and extracted from all anatomically standardized magnetic resonance images using SPM2, and they were used for partial volume correction. These databases allow the comparison of regional distributions of striatal and extrastriatal dopamine D, and D2 receptors, dopamine transporter, and endogenous dopamine synthesis capability. These distributions were in good agreement with those from human postmortem studies. This database can be used in various researches to understand the physiology of dopaminergic functions in the living human brain. This database could also be used to investigate regional abnormalities of dopaminergic neurotransmission in neuropsychiatric disorders. (C) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neuroimage.2007.09.011

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記述言語：日本語   出版者・発行元：(一社)日本核医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

N-methyl-D-aspartate (NMDA) receptors are of major interest in brain functions and neuropsychiatric disorders. However, at present there are few suitable radioligands for in vivo imaging of NMDA receptors. 7-Choloro-4-hydroxy-3[3-(4-methoxybenzyl) phenyl]-2(1H)-quinolone (L-703,717) is one of the potent ligands for the glycine-binding site of NMDA receptors. 4-Acetoxy derivative of L-703,717 (AcL703) is a candidate, as a positron emission tomography (PET) ligand for NMDA receptors, because of its better permeability at the blood-brain barrier compared with L-703,717. After intravenous injection of 624-851 MBq of [C-11]AcL703, dynamic PET scan was performed on six healthy males for 90 min. Regions-of-interest were located on the cerebral cortices, cerebellar cortex, and cerebral white matter. The binding potential (BP) was calculated from the ratio of the area under the curve (AUC) of radioactivities from 40 to 90 min in the target region to that in white matter. Regional radioactivities reached close to equilibrium in all regions after about 40 min postinjection. Regional brain uptake of [C-11]AcL703 at 40 min after injection was 0.00028-0.00065% of the injected dose/milliliter. Radioactivity concentration of [C-11]AcL703 was highest in the cerebellar cortex and lowest in white matter. AUC in the cerebellar cortex was higher than those of cerebral cortices, thalamus, striatum, and white matter. BP in the cerebellar cortex was twofold higher than in the cerebral cortices (cerebellar cortex: BP = 2.20 +/- 0.72; cerebral cortices: BP = 1.05 +/- 0.45). Despite the low brain uptake of [C-11]AcL703, regional distributions were in good agreement with our previous studies of rodents. This indicates the possibility of in vivo evaluation of NMDA receptors using PET with [C-11]AcL703 in living human brain. Synapse 61:795-800, 2007. (C) 2007 Wiley-Liss, Inc.

DOI： 10.1002/syn.20415

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Background: Personality trait is thought to be one of the important factors for vulnerability to depression. The relation between serotonin transporter (5-HTT) polymorphism and anxiety-related personality has been investigated in genetic research. In this study, we investigated the relation between in vivo regional 5-HTT binding in the brain and personality inventory measures in normal male volunteers.
Methods: Thirty-one healthy male volunteers underwent positron emission tomography scans with C-11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl) benzonitrile ([C-11]DASB) to measure 5-HTT and completed revised NEO Personality Inventory. Correlation of [C-11]DASB binding potentials (BP) with personality inventory measures was calculated using region-of-interest analysis and statistical parametric mapping based on the BP images.
Results: Neuroticism was positively correlated with 5-HTT binding in the thalamus (p = .004). No significant correlation was observed in any other brain region. Within the neuroticism dimension, the facet of depression was positively correlated with 5-HTT binding in the thalamus (P = .001).
Conclusions: Subjects with higher thalamic 5-HTT binding are more likely to express higher levels of neuroticism and depressive feeling. Serotonin transporter binding in the thalamus might be a marker of vulnerability to depression.

DOI： 10.1016/j.biopsych.2006.11.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objectives C-11-WAY 100635 has been used widely in the PET research field to measure 5-HT1A receptors in the living human brain. Reference tissue model analysis, in which the cerebellum was used as the reference tissue, was employed in clinical studies. However, the reported binding potentials varied greatly among the reports. In this study, regions of interest (ROIs) of the cerebellum for C-11-WAY 100635 were determined in five different approaches for six healthy male volunteers, and the effects on binding potential parametric images were compared.
Methods First, ROIs on the cerebellar cortex were decided based on information from magnetic resonance imaging (MRI), and then divided into upper and lower parts. They were then refined according to coregistered positron emission tomography (PET) image information, generating upper-refined and lower-refined parts. In a different approach, circular ROIs were decided upon, based on the PET images, and the areas under the curve (AUCs) of five ROIs were compared. Parametric images of binding potentials were calculated with the five ROIs as the reference, and compared with each other.
Results The AUCs of the lower-refined parts were the lowest among the first four ROIs. The ratio of the AUCs between the upper part and lower-refined part was 1.54 +/- 0.17, that between the upper-refined part and lower-refined part was 1.27 +/- 0.21, that between the lower part and lower-refined part was 1.04 +/- 0.02, and that between the circular ROIs and lower-refined part was 1.01 +/- 0.04. The differences in AUCs among the five cerebellar parts led to significant differences in the binding potential parametric images.
Conclusion The binding potential parametric images of C-11-WAY100635 could vary significantly according to the different methods of establishing ROIs, using the cerebellum as the reference tissue, because radioactivity in the cerebellum for C-11-WAY100635 is very low.

DOI： 10.1097/MNM.0b013e328013ebec

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

Background and aims: Obsessive compulsive disorder (OCD) is psychiatric disorder characterized by recurrent obsessions and compulsions. Based on the selective efficacy of serotonin reuptake inhibitors (SRIs) and comorbid depression that is often observed in OCD, the serotonergic system including serotonin transporter (SERT) has been of interest in pathophysiology of OCD. Previous study using positron emission tomography (PET) with a radiotracer [11C]McN5642 for SERT failed to changes in density of SERT in OCD patients. The aim of the present study is to investigate SERT density using [11C]DASB which shows high selectivity and affinity to SERT as compared with [11C]McN5642. Methods: Ten patients with OCD, free of psychiatric medication and comorbid depression, and 18 gender and age-matched healthy subjects participate in this study. OCD was diagnosed according to the DSM-IV. OCD severity was assessed by Yale?Brown Obsessive?Compulsive Scale (Y-BOCS, scale range: 0?40). After intravenous infusion of [11C]DASB, a dynamic PET scanning was performed for 90 min. Regions-of-interest were defined on the frontal cortex, thalamus, striatum and midbrain on the coregistered magnetic resonance images. The binding potential (BP) of [11C]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2) developed by Ichise et at al. Results: As shown that Y-BOCS score was 22±7.6 (range: 7-32), the degree of severity in the present subjects varied relatively widely. BP values for OCD patients were 0.17±0.05, 1.48±0.10, 1.20±0.09, and 1.35±0.28, and values for healthy controls were 0.22±0.10, 1.60±0.24, 1.53±0.33, and 1.24±0.20 in the frontal cortex, thalamus, striatum and midbrain, respectively. No significant group differences were observed in BP of [11C]DASB in any of brain regions. No significant correlations were observed between severity of OCD and BP. Conclusions: Although SERT has been of interest in pathophysiology of OCD, no significant differences were observed in SERT density between OCD and healthy controls, same as the previous study using [11C]McN5642. OCD without comorbid depression may not be associated in only serotonergic system, but also other neurotransmission systems.

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記述言語：日本語   出版者・発行元：日本催眠学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2006191975

記述言語：日本語   出版者・発行元：日本催眠学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2006203730

記述言語：日本語   出版者・発行元：克誠堂出版(株)  

10万円前後で購入できる一般向けオートマチックのデジタルカメラ230万画素クラスのもの9種及び,300万画素クラスのもの9種と,フィルムカメラを対象に,色調の再現性を検討した.3原色各々について,撮影した写真と基準のカラーチャートとのずれを数値で表現したところ,デジタルカメラでは機種により再現性に差があったが,フィルムカメラより優れたものはなかった.又,230万画素クラスのものと300万画素クラスのものでは,明確な違いは認めなかった

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記述言語：日本語   出版者・発行元：(国研)国立精神・神経医療研究センター精神保健研究所  

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記述言語：日本語   出版者・発行元：(国研)国立精神・神経医療研究センター精神保健研究所  

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/mp.2012.7

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：NATURE PUBLISHING GROUP  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：NATURE PUBLISHING GROUP  

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記述言語：日本語   出版者・発行元：(一社)日本核医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

DOI： 10.1016/j.neuroimage.2010.04.076

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

DOI： 10.1016/j.neuroimage.2010.04.081

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：CAMBRIDGE UNIV PRESS  

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記述言語：日本語   出版者・発行元：医学書院  

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その他リンク： http://search.jamas.or.jp/link/ui/2009105176

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記述言語：日本語   出版者・発行元：アークメディア  

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その他リンク： http://search.jamas.or.jp/link/ui/2008155447

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：CAMBRIDGE UNIV PRESS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

DOI： 10.1016/j.neuroimage.2006.04.010

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開催地：国立京都国際会館（京都府）  

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開催地：沖縄コンベンションセンター（沖縄県）  

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