Positron Emission Tomography Measurement of Dopamine D2 Receptor Occupancy in the Pituitary and Cerebral Cortex: Relation to Antipsychotic-Induced Hyperprolactinemia
Objective: Hyperprolactinemia is a common side effect of antipsychotic drugs used in the treatment of schizophrenia. However, the magnitude of hyperprolactinemia differs among antipsychotics, and there is no reliable mechanism-related marker for the risk of hyperprolactinemia that would allow us to characterize antipsychotics.
Method: In this study, 11 healthy male subjects taking different doses of sulpiride and 24 male patients with DSM-IV–diagnosed schizophrenia taking different antipsychotic drugs (risperidone, olanzapine, haloperidol, and sulpiride) participated. Positron emission tomography scanning using [11C]FLB 457 was performed on all subjects. The dopamine D2 receptor occupancy of antipsychotics in the pituitary and temporal cortex was calculated. Correlations between plasma concentration of prolactin and dopamine D2 receptor occupancies were evaluated. The ratio of drug concentration of cerebral receptor site to that of pituitary receptor site (brain/plasma concentration ratio; B/P ratio) was calculated from the receptor occupancies in the 2 regions. Data were collected between November 2001 and September 2007.
Results: Significant positive correlation was observed between the plasma concentration of prolactin and dopamine D2 receptor occupancy in the pituitary by all 4 antipsychotics (P = .001). Dopamine D2 receptor occupancies of sulpiride were markedly different between the pituitary and temporal cortex, and the B/P ratio for sulpiride (0.34) was significantly lower than for olanzapine (P = .007) and risperidone (P = .015). Olanzapine had a relatively high B/P ratio (2.70), followed by haloperidol (2.40) and risperidone (1.61).
Conclusions: Dopamine D2 receptor occupancy in the pituitary is a good indicator of hyperprolactinemia. B/P ratio, indicating the penetrating capability across the blood-brain barrier, seems to be a good characteristic biomarker of each antipsychotic drug for the risk of hyperprolactinemia at therapeutic dose.
J Clin Psychiatry 2010;71(9):1131–1137
© Copyright 2010 Physicians Postgraduate Press, Inc.
Submitted: April 17, 2008; accepted April 15, 2009.
Online ahead of print: February 23, 2010 (doi:10.4088/JCP.08m04307yel).
Corresponding author: Tetsuya Suhara, MD, PhD, Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences 4-9-1, Anagawa, Inage-ku, Chiba, 263-8555, Japan (firstname.lastname@example.org).
Hyperprolactinemia is a commonly encountered side effect of antipsychotic drugs in the treatment of schizophrenia,1,2 and several deficits, such as galactorrhea and sexual dysfunction, can result. For women, amenorrhea and infertility are severe adverse effects, and long-term hyperprolactinemia causes osteoporosis in relation to hypogonadism.1,3 Hyperprolactinemia is one of the major reasons for discontinuing antipsychotic drugs,4 but the risk for this condition varies among them.5–8 It has been reported that antipsychotics such as risperidone and amisulpride showed a high risk, and several factors have been discussed in relation to this risk,5–9 such as affinity for dopamine D2 receptors6,8 and the pharmacodynamics in plasma and brain.9
Prolactin secretion is controlled by tonic inhibition of dopamine on tuberoinfundibular neurons.10,11 Hyperprolactinemia is reported to be induced by the blocking of dopamine D2 receptors in the pituitary. As the pituitary is located outside of the blood-brain barrier, drug effects on dopamine D2 receptors would differ between it and the brain parenchyma.9 However, there has been no report about this relation in the living human brain.
Previous positron emission tomography (PET) studies focused on extrapyramidal side effects of antipsychotics induced by over 80% of striatal dopamine D2 receptor occupancy.12–14 Since dopamine D2 receptor density in the pituitary is low (Bmax = 1.3 pmol/g tissue) compared to the striatum (Bmax = 16.6 pmol/g tissue),15 measurement of dopamine D2 receptor binding in the pituitary is difficult using a radioligand with relatively low affinity such as [11C]raclopride. [11C]FLB 457 has very high affinity for dopamine D2 receptors,16 and since it is used to measure dopamine D2 receptors in extrastriatal regions where their density is very low,17–21 it can also be used to measure dopamine D2 receptor binding in the pituitary. Although some studies have reported the visualization or occupancy of human pituitary dopamine D2 receptors,22–24 the quantification of dopamine D2 receptor occupancy in the pituitary by several antipsychotics using PET has not been reported.
In this study, we aimed to investigate biomarkers for the potential risk of antipsychotic drug–induced hyperprolactinemia in the living human brain. Dopamine D2 receptor occupancies in the pituitary and temporal cortex were measured using [11C]FLB 457 by different doses of sulpiride in healthy subjects to examine the dose-occupancy relationship in the 2 regions and by various antipsychotic drugs in patients with schizophrenia to examine the relation with hyperprolactinemia.
Subjects and Study Protocol
Study of healthy subjects receiving different doses of sulpiride. Eleven healthy male subjects (age range, 21–40 years; mean ± SD = 27.1 ± 5.8 years) participated in this study. Two PET scans using [11C]FLB 457 were performed before and 3 hours after a single dose of sulpiride at 200 mg (n = 3), 400 mg (n = 3), 600 mg (n = 3), and 800 mg (n = 2). Just before the second PET scan, venous blood samples were taken to measure the plasma concentration of prolactin.
Study of patients with schizophrenia receiving different antipsychotics. Twenty-four male patients (age range, 21–49 years; mean ± SD = 37.1 ± 8.9 years) diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)25 criteria participated in this study. Exclusion criteria were current or past substance abuse, organic brain disease, or epilepsy. Subjects with severe liver or renal dysfunction or who had undergone electroconvulsive therapy within 90 days prior to this study were also excluded. The patients had been taking 1 oral antipsychotic drug at fixed dosage for at least 2 weeks before the start of this study (range, 2 weeks to 11 years; mean, 25 months). Seven patients took risperidone at 2 mg (n = 2), 4 mg (n = 4), and 6 mg (n = 1); 7 patients took olanzapine at 5 mg (n = 2), 10 mg (n = 3), 15 mg (n = 1), and 20 mg (n = 1); 4 patients took haloperidol at 6 mg (n = 2), 9 mg (n = 1), and 12 mg (n = 1); and 6 patients took sulpiride at 200 mg (n = 2), 400 mg (n = 2), 600 mg (n = 1), and 900 mg (n = 1). Antipsychotic treatment was continued during the performance of the PET scans using [11C]FLB 457. The duration between PET scan and the last administration of antipsychotic drug was between 2 hours and 20 hours. Just before PET scan, venous blood samples were taken to measure the plasma concentration of prolactin.
After complete description of this study, written informed consent was obtained from all subjects. The study was approved by the Ethics and Radiation Safety Committee of the National Institute of Radiologic Sciences, Chiba, Japan. Data were collected between November 2001 and September 2007.
Positron Emission Tomography Procedure
A PET scanner system, ECAT EXACT HR+ (CTI-Siemens, Knoxville, Tennessee), was used for all subjects. A head fixation device was used to minimize head movement. A transmission scan for attenuation correction was performed using a 68Ge-68Ga source before each scan. Dynamic PET scan was performed for 90 minutes after intravenous bolus injection of 155.0–240.1 MBq (mean ± SD = 228.5 ± 72.5 MBq) of [11C]FLB 457. The specific radioactivity of [11C]FLB 457 was 81.6–339.9 GBq/μmol (174.8 ± 63.4 GBq/μmol). Magnetic resonance images (MRIs) of the brain were acquired with 1.5 Tesla MRI, Gyroscan NT (Philips Medical Systems, Best, The Netherlands). T1-weighted images were obtained at 1-mm slices. All subjects were free of organic brain or pituitary lesions.
All emission scan data were reconstructed with a Hanning filter. Regions of interest (ROIs) were defined for the pituitary, temporal cortex, and cerebellar cortex. The ROIs were drawn manually on PET images with reference to the individual magnetic resonance images. The values of ROIs for the right and left sides were averaged. The temporal cortex was used as the representative brain region because there was little difference in dopamine D2 receptor occupancy among extrastriatal brain regions.26 Binding potential (BPND) of dopamine D2 receptors was calculated from the ratio of the area under the time-activity curve (AUC):
BPND = (AUCregion / AUCcerebellum) – 1 (Equation 1).
The subscript “region” denotes the pituitary and temporal cortex. The cerebellum was used as reference tissue given its negligible density of dopamine D2 receptors.27 In this study, an integration interval of 60 to 90 minutes was used for the calculation of AUC.20
The receptor occupancy of antipsychotic drug is expressed as follows14:
Occupancy (%) = (BPbaseline - BPdrug) / BPbaseline x 100 (Equation 2),
in which BPbaseline is the baseline BPND in the drug-free state and BPdrug is BPND after the administration of antipsychotic drug. In the healthy subjects study, both BPND values obtained from each individual were used. In the patients study, the mean BPND of 15 age-matched healthy male subjects (age range, 21–49 years, mean ± SD = 34.2 ± 8.4 years) was used as BPbaseline because of the lack of individual baseline BPND values. There was no difference in age between healthy subjects and patients (2-tailed t test; P = .32). There was no age effect of BPND in the temporal cortex (P = .37) and pituitary (P = .61) within this age range (21–49 years) of healthy subjects.
The relationship between receptor occupancy and antipsychotic drug dose can be expressed as follows18,21:
Occupancy (%) = D / (D + ED50) × 100 (Equation 3),
in which D is the dose of drug and ED50 is the dose required to induce 50% occupancy.
We calculated the ratio of drug concentration in the cerebral cortex to that in plasma (brain/plasma ratio; B/P ratio), which indicates the penetrating capability of antipsychotic drugs across the blood-brain barrier. Equation 3 can be rewritten as follows:
C = IC50 / ([100 / Occupancy] − 1)(Equation 4),
in which C is the drug concentration in the brain or plasma. IC50 is the drug concentration required to induce 50% occupancy, reflecting the affinity of each antipsychotic drug to dopamine D2 receptor, and, therefore, IC50 can be assumed to be the same value between the pituitary and the temporal cortex. Because the pituitary exists outside the blood-brain barrier, the B/P ratio can be expressed as follows:
B/P ratio = Cbrain / Cpituitary = ([100 / Occupancypituitary] − 1) /
([100/Occupancytemporal] − 1) (Equation 5),
in which Cpituitary is the drug concentration in the vicinity of receptors in the pituitary, and Cbrain is the drug concentration in the vicinity of receptors in the temporal cortex. Occupancypituitary is the dopamine D2 receptor occupancy in the pituitary, and Occupancytemporal is that in the temporal cortex. The B/P ratio of each antipsychotic drug was calculated.
The plasma concentration of prolactin was measured by chemiluminescent immunoassay at a commercial laboratory (SRL Inc, Tokyo, Japan). The normal range for males is 3.6–12.8 ng/mL. Values exceeding 12.8 ng/mL were defined as hyperprolactinemia.
A simulation study was performed in order to estimate the relationship between the B/P ratio and prolactin. First, pituitary occupancy was calculated by Equation 5 according to changes in the B/P ratio when occupancy in the temporal cortex was set at 60%, 70%, and 80%, which was the range of clinical dosage.12–14 Next, assumed prolactin values were estimated using linear regression obtained from the patients study. The measured prolactin values in patients (mean temporal cortex occupancy, 66.5 ± 13.9%) were plotted in this simulation graph against the mean B/P ratio of each antipsychotic drug.
Correlations between plasma concentration of prolactin and dopamine D2 receptor occupancy in the pituitary or temporal cortex by the 4 antipsychotic drugs were evaluated using Pearson correlation coefficient. The relationship between occupancy in the pituitary and hyperprolactinemia was evaluated using Fisher exact test. Group differences of B/P ratio among the 4 antipsychotics were evaluated by Kruskal-Wallis test. Multiple comparisons of B/P ratio between the respective antipsychotics were evaluated using the Mann-Whitney U test with Ryan method.
Study of Healthy Subjects Receiving Different Doses of Sulpiride
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Dopamine D2 receptor occupancy in the pituitary by sulpiride ranged from 78.4% to 103.2% (mean ± SD = 96.1 ± 4.6% for 200 mg, 97.1 ± 6.1% for 400 mg, 80.3 ± 1.9% for 600 mg, and 91.1 ± 4.2% for 800 mg), and the occupancy in the temporal cortex ranged from 15.2% to 71.9% (25.4 ± 9.3% for 200 mg, 54.0 ± 21.8% for 400 mg, 55.9 ± 2.9% for 600 mg, and 54.8 ± 17.5% for 800 mg) (Figure 1). ED50 for the pituitary was 22.2 mg and for the temporal cortex was 475.6 mg. The plasma concentration of prolactin ranged from 19.1 to 41.7 ng/mL. The plasma concentration of prolactin for all subjects reached the level of hyperprolactinemia.
Figure 2 shows the mean values of the time-activity curves of the pituitary (predose and postdose of sulpiride), temporal cortex (predose), and cerebellum of the 11 healthy subjects. The curve of the pituitary at postdose was decreased to a level similar to that of the cerebellum.
Study of Patients Receiving Different Antipsychotics
Dopamine D2 receptor occupancies in the pituitary by risperidone, olanzapine, haloperidol, and sulpiride were 49.2%–80.1%, 18.6%–79.5%, 27.2%–104.4%, and 68.9%–108.4%, respectively, and those in the temporal cortex were 53.4%–79.5%, 50.7%–76.2%, 66.9%–83.2%, and 26.9%–81.8%, respectively. Plasma concentrations of prolactin of patients with risperidone, olanzapine, haloperidol, and sulpiride were 8.9 to 39.9 ng/mL, 3.5 to 23.0 ng/mL, 4.7 to 22.7 ng/mL, and 34.7 to 57.4 ng/mL, respectively. The percentages of hyperprolactinemia of olanzapine, haloperidol, risperidone, and sulpiride were 29% (2/7), 50% (2/4), 86% (6/7), and 100% (6/6), respectively.
Significant positive correlation was observed between the plasma concentration of prolactin and dopamine D2 receptor occupancy in the pituitary by the 4 antipsychotic drugs (Y = 0.41X – 4.0; r = 0.62; P = .001) (Figure 3). However, no correlation was found between the plasma concentration of prolactin and dopamine D2 receptor occupancy in the temporal cortex by the 4 antipsychotic drugs (r = –0.097; P = .65) (Figure 4). When the threshold was set with every 10% of occupancy in the pituitary, patients with hyperprolactinemia could be estimated using Fisher exact test at 50% with the lowest P value (P = .005).
The B/P ratio of the 4 antipsychotics differed significantly (χ23 = 8.54; P = .036). The mean ± SD B/P ratios of olanzapine, haloperidol, risperidone, and sulpiride were 2.70 ± 1.84, 2.40 ± 2.40, 1.61 ± 1.00, and 0.34 ± 0.42, respectively (Figure 5), the same order as the percentages of hyperprolactinemia. The B/P ratios were significantly different in olanzapine versus sulpiride (U = 2; P = .007 < 0.05/6) and risperidone versus sulpiride (U = 4; P = .015 < 0.05/2), but haloperidol versus sulpiride did not reach significance (U = 6; P = .20). Figure 6 shows the PET images of 1 healthy subject and 2 patients, 1 taking olanzapine and the other sulpiride. Sulpiride blocked dopamine D2 receptors to a greater extent in the pituitary than in the temporal cortex, and olanzapine showed relatively less effect in the pituitary.
In the simulation study, drugs with a low B/P ratio induced a high prolactin level at clinical doses with 60%–80% of dopamine D2 receptor occupancy in the temporal cortex. The measured prolactin values of patients also showed the same tendency (Figure 7). The simulated plasma prolactin level increased when the set value of occupancy in the temporal cortex was increased.
In the present study healthy subjects treated with different doses of sulpiride, a marked difference in dopamine D2 receptor occupancy was confirmed between the pituitary and temporal cortex using the baseline of each. Dopamine D2 receptors in the pituitary were almost fully occupied even at the lowest dose (200 mg), at which occupancy in the temporal cortex was around 25% (Figure 1). Lipophilicity is a major determinant of the penetrating ability into the brain.28 Since the log P value of sulpiride is reported to be 0.42–1.31, the low brain uptake was considered to be due to lower lipophilicity.29,30
Although nonspecific binding in the pituitary may not be the same as that of the brain parenchyma, the fully occupied time-activity curve of the pituitary was at almost the same level as that of the cerebellum (Figure 2), suggesting that the cerebellum could be used as a measure of nonspecific binding in the pituitary. In the calculation of BPND in the pituitary, we used the AUC ratio method, which does not require the assumptions that are required for the simplified reference tissue model method (SRTM). The effect of the radiolabeled metabolite of [11C]FLB 457 would be small for the measurement of dopamine D2 receptors in the pituitary because a previous study indicated that a major metabolite of [11C]FLB 457 had very low affinity for dopamine D2 receptors.16 The BPND values in the temporal cortex were measured by the same method. Binding potential in the extrastriatum by AUC ratio method showed good correlation with those by indirect kinetic method (reported value; r = 0.96).20 Although some subjects did not reach equilibrium in the pituitary in this study, the mean value of BPND in the pituitary was 2.11, almost the same as the reported value in the temporal cortex (2.23) and less than that in the thalamus (3.67), suggesting that the equilibrium would be around the measured time range. Furthermore, the occupancies in the pituitary of patients (n = 24) calculated by the SRTM method showed good correlation with those by the AUC ratio method (r = 0.94, data not shown). These data suggested that the AUC ratio method can also be used for quantification of the pituitary.
The present study demonstrated that dopamine D2 receptor occupancy in the pituitary by 4 antipsychotic drugs was significantly correlated with the plasma concentration of prolactin (Y = 0.41X – 4.0; P = .001) (Figure 3), but no such correlation was found in the temporal cortex (Figure 4). It has been reported that hyperprolactinemia was induced when dopamine D2 receptor occupancy in the striatum exceeded 50% for raclopride31 and 72% for haloperidol.12 However, no correlation was reported between hyperprolactinemia and striatal or temporal cortex occupancy by amisulpride.32 In this study using Fisher exact test, the patients with hyperprolactinemia could be estimated at 50% with the lowest P value (P = .005). This indicated that 50% of dopamine D2 receptor occupancy in the pituitary might represent a threshold level of hyperprolactinemia.
The magnitude of hyperprolactinemia differs among antipsychotics. It has been reported that atypical antipsychotics showed a low risk of hyperprolactinemia as compared to typical antipsychotics.1,5,7 Although olanzapine, clozapine, and quetiapine reportedly showed a relatively low risk,5–8 risperidone and amisulpride, regarded as atypical antipsychotics, presented a high risk.5–8,32 This difference was discussed in relation to the affinity to dopamine D2 receptors.6,8 Risperidone has relatively high affinity, whereas those of olanzapine, clozapine, and quetiapine are medium or low.33 This order is apparently in accordance with the risk of hyperprolactinemia, although amisulpride has a high risk despite its medium affinity.33 Thus, after all, the affinity for dopamine D2 receptors could not conclusively explain the risk of hyperprolactinemia.
A previous animal study suggested that the dissociation between central and peripheral dopamine D2 receptor occupancy could be a marker of prolactin elevation.9 The reported ED50 ratios of the pituitary to the striatum were 654 for amisulpride, 11 for risperidone, and 0.7 for olanzapine, indicating that their respective permeabilities were low, medium, and high. In this study, we calculated the B/P ratio defined as the ratio of antipsychotic drug concentration at the temporal cortex receptor site to that at the pituitary receptor site to explain the ED50 difference between that in the pituitary and the temporal cortex. It was based on the assumption of fixed IC50, although several factors should be considered concerning the IC50 determination. First, endogenous dopamine may affect the BPND values of [11C]FLB 457. Some studies reported that dopamine manipulation such as amphetamine challenge did not change BPND,34–36 but other studies reported a different conclusion.37–42 In this study, we assumed that, compared with amphetamine challenge, antipsychotic drug did not substantially change endogenous dopamine. Second, antipsychotic concentration change during the PET scan may affect the occupancy values according to a previous study.24 Our previous studies reported that there was no regional difference of dopamine D2 receptor occupancy between the striatum and extrastriatum.43 Moreover, dopamine D2 receptor densities showed similar values between the temporal cortex and pituitary (Bmax = 0.4 and 1.3 pmol/g tissue, respectively).15 In this study, the drug washout rate could be ignored because patient treatment was in the steady-state and receptor densities were close between the 2 sites. Taken together, we assumed that IC50 values were the same between the pituitary and the temporal cortex, and that the antipsychotic drug concentration difference could be estimated.
The order of the B/P ratio in our results was consistent with that of the ED50 ratio in the above-mentioned animal study. The B/P ratio can be the characteristic index of antipsychotic drugs. The concentration of sulpiride in the temporal cortex was one-third of that in the pituitary, while those of olanzapine and haloperidol were about double or triple. Sulpiride had significantly low permeability compared to risperidone (P = .015) and olanzapine (P = .007), indicating the high risk of hyperprolactinemia for sulpiride.5 Although no significant difference of B/P ratio between haloperidol and sulpiride was observed, possible reasons were small sample size and large SD. The order of the B/P ratio was the same as the percentage of hyperprolactinemia in this study. In the simulation study, a drug with low B/P ratio induced a high prolactin level at clinical dosage with 60%–80% of dopamine D2 receptor occupancy in the temporal cortex (Figure 7). The measured prolactin values of patients showed a similar tendency to the simulated ones. Thus, the B/P ratio seems to be a useful index for predicting the risk of each antipsychotic drug for hyperprolactinemia.
Brain permeability differences are the result of several factors. The Log P values of risperidone, olanzapine, and haloperidol are 3.04, 2.89, and 3.36–3.52, respectively,30,44,45 and the higher permeability of risperidone, olanzapine, and haloperidol compared to sulpiride (or amisulpride; Log P = 1.10–1.7029,45) can be ascribed to high lipophilicity. However, risperidone, in fact, has a slightly higher Log P value than olanzapine despite its slightly lower permeability, a seeming contradiction explainable by the fact that risperidone is reportedly a substrate of P-glycoprotein, one of the efflux transporters at the blood-brain barrier.46,47
There were several confounding factors in this study. In the patients study, we used the mean BPND of healthy control subjects as baseline because previous studies showed no differences in dopamine D2 receptors in the temporal cortex between patients and healthy subjects17,19 or lower binding in patients.48,49 A variety of baseline BPND values can lead to large SD of occupancy or B/P ratio. For example, if BPbase changes by ± 15%,17 the calculated 50% occupancy could be changed from 41% to 57%. The variety would affect the statistics significantly, especially with the small number of subjects like the haloperidol cases. Furthermore, possible change in the pituitary of patients with schizophrenia50 could lead to potential errors in the estimation of occupancy values.
In conclusion, dopamine D2 receptor occupancies in the pituitary by 4 different antipsychotics were well correlated with the plasma concentration of prolactin. The B/P ratios of the 4 antipsychotics were significantly different. The magnitude of hyperprolactinemia of various antipsychotics can be predicted by the B/P ratio, which indicates the permeability of antipsychotics into the brain. Thus, especially in the area of new drug development, the B/P ratio of each antipsychotic drug might prove to be useful for the early evaluation of the risk of hyperprolactinemia.
Drug names: clozapine (FazaClo, Clozaril, and others), haloperidol (Haldol and others), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal and others).
Author affiliations: Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan (Drs Arakawa, Okumura, Ito, A. Takano, Takahashi, H. Takano, Maeda, and Suhara); and Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan (Drs Arakawa, Okumura, and Okubo).
Potential conflicts of interest: The authors have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article.
Funding/support: This study was supported by a consignment expense for the Molecular Imaging Program on “Research Base for Positron Emission Tomography (PET) Diagnosis” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japanese Government.
Role of sponsor: The sponsors of the study had no role in the study design, collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
Acknowledgment: We thank Mr Katsuyuki Tanimoto, BS, Mr Takahiro Shiraishi, BS, Mr Akira Ando, BS, and Mr Toshio Miyamoto, BS, from the National Institute of Radiological Science in Chiba, Japan, for their assistance in performing the PET experiments, Mr Takashi Okauchi, BS, from the National Institute of Radiological Science in Chiba, Japan, for advice on the statistics, and Ms Yoshiko Fukushima, BS, from the National Institute of Radiological Science in Chiba, Japan, for her help as clinical research coordinator at the National Institute of Radiological Sciences. We also thank Dr Jun Kosaka, MD, from the Sobu Hospital in Chiba, Japan, and Dr Amane Tateno, MD, PhD, Dr Mizuho Sekine, MD, and Dr Hajime Fukuta, MD, from the Nippon Medical School in Tokyo, Japan, for their clinical support. All acknowledged individuals have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article.
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