Improved Correlation of 18F-Flortaucipir PET SUVRs and Clinical Stages in the Alzheimer Disease Continuum with the MUBADA/PERSI-Based Analysis.

The Alzheimer disease (AD) continuum is a neurodegenerative disorder with cognitive decline and pathologic changes. Tau PET imaging can detect tau pathology, and 18F-flortaucipir PET imaging is expected to visualize progression through the stages of AD, for which quantitative assessment is essential. Two measurement methods, statistically defined multiblock barycentric discriminant analysis (MUBADA)/parametric estimation of reference signal intensity (PERSI) and anatomically defined tau meta-volume of interest (VOI)/cerebellar gray matter (CGM) for SUV ratio (SUVR), were compared in this study to assess their relationship to AD clinical stage using 2 open multicenter PET databases. Methods: Data were selected for 106 cases from 2 databases, AMED Preclinical AD study (AMED-PRE) (n = 15) and Alzheimer Disease Neuroimaging Initiative 3 (n = 91). The data of the participants were categorized into 4 groups based on the clinical criteria. Tau PET imaging was conducted using 18F-flortaucipir, and the 2 SUVR measurement methods, MUBADA/PERSI and tau meta-VOI/CGM, were compared among different clinical categories: amyloid-negative cognitively normal, preclinical AD, amyloid-negative mild cognitive impairment (MCI), and amyloid-positive MCI. Results: Significant differences were found between cognitively normal and preclinical AD, as well as between cognitively normal and amyloid-positive MCI and between amyloid-negative MCI and -positive MCI in SUVR derived by MUBADA/PERSI, whereas SUVR by tau meta-VOI/CGM did not provide significant differences between any pair. The tau meta-VOI/CGM method consistently provided higher SUVRs and larger individual variations than MUBADA/PERSI, with a mean SUVR difference of 0.136 for the studied databases. Conclusion: MUBADA/PERSI provided the SUVR of 18F-flortaucipir uptake with better association with the clinical severity of the AD continuum and with smaller variability. The results support the usefulness of MUBADA/PERSI as a quantitative measure of 18F-flortaucipir uptake in multicenter studies using different PET systems and scanning methods. However, limitations of the study include the small sample size and the unbalanced distribution among clinical categories in the AMED Preclinical AD study database.

[Accuracy of Injection Dose of Amyloid PET Agent Using Radiopharmaceutical Activity Suppliers].

PURPOSE: This study aimed to identify disposable items with low amyloid positron emission tomography (PET) agent radioactivity adsorption for accurate injections using a radiopharmaceutical activity supplier. METHODS: First, we investigated disposable items currently used for amyloid PET agent injection. Next, we measured the residual radioactivity rates of amyloid PET agents on three-way stopcocks, extension tubes, butterfly needles, and indwelling needles to identify disposable items with low radioactivity adsorption. Finally, we evaluated the accuracy of amyloid PET agent injection using the selected disposable items and a radiopharmaceutical activity supplier. RESULTS: The polybutadiene extension tube exhibited a significantly lower residual activity rate than that of the polyvinyl chloride extension tube. Similarly, the indwelling needles showed significantly lower residual activity rate than that of butterfly needles. The dose indicated by a radiopharmaceutical activity supplier was 184.1 MBq, while the dose calibrator measured the radioactivity which flowed into the vial as 170.2 MBq, resulting in an administration accuracy of 8.2%. CONCLUSION: To ensure accurate amyloid PET agent injections, we recommend using polybutadiene extension tubes and indwelling needles due to their lower radioactivity adsorption.

Dosimetry and efficacy of a tau PET tracer [18F]MK-6240 in Japanese healthy elderly and patients with Alzheimer's disease.

OBJECTIVE: A new tau PET tracer [18F]MK-6240 has been developed; however, its dosimetry and pharmacokinetics have been published only for a European population. This study investigated the safety, radiation dosimetry, pharmacokinetics and biodistribution of [18F]MK-6240 in Japanese elderly subjects. Also, the pattern and extent of brain retention of [18F]MK-6240 in Japanese healthy elderly subjects and patients with Alzheimer's disease (AD) were investigated. These Japanese results were compared with previous reports on non-Japanese. METHODS: Three healthy elderly subjects and three AD patients were enrolled. Dynamic whole-body PET scans were acquired for up to 232 min after starting injection of [18F]MK-6240 (370.4 ± 27.0 MBq) for the former, while a dynamic brain scan was performed from 0 to 75 min post injection for the latter. For both groups, brain PET scans were conducted from 90 to 110 min post injection. Sequential venous blood sampling was performed to measure the radioactivity concentration in the whole blood and plasma as well as the percentages of parent [18F]MK-6240 and radioactive metabolites in plasma. Organ doses and effective doses were estimated using the OLINDA Ver.2 software. Standardized uptake value ratios (SUVRs) and distribution volume ratios (DVRs) by Logan reference tissue model (LRTM) were measured in eight brain regions using the cerebellar cortex as the reference. Blood tests, urine analysis, vital signs and electrocardiography were performed for safety assessments. RESULTS: No adverse events were observed. The highest radiation doses were received by the gallbladder (257.7 ± 74.9 µGy/MBq) and the urinary bladder (127.3 ± 11.7 µGy/MBq). The effective dose was 26.8 ± 1.4 µSv/MBq. The parent form ([18F]MK-6240) was metabolized quickly and was less than 15% by 35 min post injection. While no obvious accumulation was found in the brain of healthy subjects, focal accumulation of [18F]MK-6240 was observed in the cerebral cortex of AD patients. Regional SUVRs of the focal lesions in AD patients increased gradually over time, and the difference of SUVRs between healthy subjects and AD patients became large and stable at 90 min after injection. High correlations of SUVR and DVR were observed (p < 0.01). CONCLUSION: The findings supported safety and efficacy of [18F]MK-6240 as a tau PET tracer for Japanese populations. Even though the number of subjects was limited, the radiation dosimetry profiles, pharmacokinetics, and biodistribution of [18F]MK-6240 were consistent with those for non-Japanese populations. TRIAL REGISTRATION: Japan Pharmaceutical Information Center ID, JapicCTI-194972.

New standards for phantom image quality and SUV harmonization range for multicenter oncology PET studies.

Not only visual interpretation for lesion detection, staging, and characterization, but also quantitative treatment response assessment are key roles for 18F-FDG PET in oncology. In multicenter oncology PET studies, image quality standardization and SUV harmonization are essential to obtain reliable study outcomes. Standards for image quality and SUV harmonization range should be regularly updated according to progress in scanner performance. Accordingly, the first aim of this study was to propose new image quality reference levels to ensure small lesion detectability. The second aim was to propose a new SUV harmonization range and an image noise criterion to minimize the inter-scanner and intra-scanner SUV variabilities. We collected a total of 37 patterns of images from 23 recent PET/CT scanner models using the NEMA NU2 image quality phantom. PET images with various acquisition durations of 30-300 s and 1800 s were analyzed visually and quantitatively to derive visual detectability scores of the 10-mm-diameter hot sphere, noise-equivalent count (NECphantom), 10-mm sphere contrast (QH,10 mm), background variability (N10 mm), contrast-to-noise ratio (QH,10 mm/N10 mm), image noise level (CVBG), and SUVmax and SUVpeak for hot spheres (10-37 mm diameters). We calculated a reference level for each image quality metric, so that the 10-mm sphere can be visually detected. The SUV harmonization range and the image noise criterion were proposed with consideration of overshoot due to point-spread function (PSF) reconstruction. We proposed image quality reference levels as follows: QH,10 mm/N10 mm ≥ 2.5 and CVBG ≤ 14.1%. The 10th-90th percentiles in the SUV distributions were defined as the new SUV harmonization range. CVBG ≤ 10% was proposed as the image noise criterion, because the intra-scanner SUV variability significantly depended on CVBG. We proposed new image quality reference levels to ensure small lesion detectability. A new SUV harmonization range (in which PSF reconstruction is applicable) and the image noise criterion were also proposed for minimizing the SUV variabilities. Our proposed new standards will facilitate image quality standardization and SUV harmonization of multicenter oncology PET studies. The reliability of multicenter oncology PET studies will be improved by satisfying the new standards.

[Report in 2018 April ～ 2020 March].

To establish a feasible and practical methodology for harmonization of FDG-PET, we have investigated quantitative physical performance of recent clinical PET scanners (23 scanners) using the NEMA image quality phantom. Compared with the previous phantom data (13 scanners) acquired in the early 2000s, the current phantom data showed better contrasts of small spheres even with a smaller number of coincidence counts. This result suggests that clinical PET image quality and small lesion detectability might have been significantly improved in the past 10 years. Based on the data acquired in this working group, we are planning to update the standard phantom test methodology and harmonizing criteria for FDG-PET.

Voxel-based statistical analysis and quantification of amyloid PET in the Japanese Alzheimer's disease neuroimaging initiative (J-ADNI) multi-center study.

BACKGROUND: Amyloid PET plays a vital role in detecting the accumulation of in vivo amyloid-ß (Aß). The quantification of Aß accumulation has been widely performed using the region of interest (ROI)-based mean cortical standardized uptake value ratio (mcSUVR). However, voxel-based statistical analysis has not been well studied. The purpose of this study was to examine the feasibility of analyzing amyloid PET scans by voxel-based statistical analysis. The results were then compared to those with the ROI-based mcSUVR. In total, 166 subjects who underwent 11C-PiB PET in the J-ADNI multi-center study were analyzed. Additionally, 18 Aß-negative images were collected from other studies to form a normal database. The PET images were spatially normalized to the standard space using an adaptive template method without MRI. The mcSUVR was measured using a pre-defined ROI. Voxel-wise Z-scores within the ROI were calculated using the normal database, after which Z-score maps were generated. A receiver operating characteristic (ROC) analysis was performed to evaluate whether Z-sum (sum of the Z-score) and mcSUVR could be used to classify the scans into positive and negative using the central visual read as the reference standard. PET scans that were equivocal were regarded as positive. RESULTS: Sensitivity and specificity were respectively 90.8% and 100% by Z-sum and 91.8% and 98.5% by mcSUVR. Most of the equivocal scans were subsequently classified by both Z-sum and mcSUVR as false negatives. Z-score maps correctly delineated abnormal Aß accumulation over the same regions as the visual read. CONCLUSIONS: We examined the usefulness of voxel-based statistical analysis for amyloid PET. This method provides objective Z-score maps and Z-sum values, which were observed to be helpful as an adjunct to visual interpretation especially for cases with mild or limited Aß accumulation. This approach could improve the Aß detection sensitivity, reduce inter-reader variability, and allow for detailed monitoring of Aß deposition. TRIAL REGISTRATION: The number of the J-ADNI study is UMIN000001374.

Image quality and variability for routine diagnostic FDG-PET scans in a Japanese community hospital: current status and possibility of improvement.

PURPOSE: In Japan, commercially delivered FDG is manufactured in three batches per day at fixed constant activity and distributed in vials. Consequently, the amount of activity administered to the patient varies depending on the timing of injection. We evaluated a method for adjusting the scan time according to the body mass index (BMI) to obtain equivalent image quality for every patient. METHODS: We examined a total of 301 routine clinical oncology PET scans using commercially delivered FDG. The relation between the injected activity and the noise equivalent count per scan length (NECpatient) was evaluated as a marker of image quality; its association with BMI was also examined. RESULTS: The injected activity and NECpatient exhibited large variations (230.4 ± 55.8 MBq and 19.9 ± 2.9 Mcounts/m). There was a weak correlation between the injected activity and NECpatient (r ~ 0.3) for thin patients (BMI < 21 kg/m(2)), but no correlation for patients with higher BMIs. However, a significant correlation was found between BMI and NECpatient (p < 0.0001). CONCLUSION: In a community hospital using commercially delivered FDG, it is possible to reduce the variability of the NECpatient and obtain uniform image quality by changing the scan time as a function of patient BMI, even with uncontrollable injected activity.

The reproducibility of time-of-flight PET and conventional PET for the quantification of myocardial blood flow and coronary flow reserve with (13)N-ammonia.

BACKGROUND: This study aimed to validate the reproducibility of quantitative analysis using time-of-flight (TOF) and conventional PET with (13)N-ammonia ((13)N-NH3). METHODS AND RESULTS: Phantom images were reconstructed with and without TOF, and recovery coefficients (RCs) and the percent contrast of each sphere over the percent background variability were assessed. In the clinical study, 21 subjects underwent dynamic (13)N-NH3 PET scanning under stress and rest conditions. The dynamic acquisition images and intra- and inter-observer reproducibility of myocardial blood flow (MBF) and coronary flow reserve (CFR) were compared between reconstructions (with and without TOF). In the phantom study, RCs and the percent contrast of each sphere over the percent background variability was improved with TOF. In the clinical study, the noise of blood pool and myocardial images with TOF was less than that without TOF. Territorial and global intra- and inter-observer reproducibility of MBF and CFR values was excellent. Although segmental intra- and inter-observer reproducibility was excellent, there were larger variations in apex and the segment near the right ventricle (RV) without TOF. These variations became inconspicuous with TOF. CONCLUSION: Visual image quality, RCs, and percent contrast over percent background variability with TOF were better than that without TOF. Excellent correlations and good agreements in quantitative values were observed. TOF improved the variation of segmental values.

Japanese guideline for the oncology FDG-PET/CT data acquisition protocol: synopsis of Version 2.0.

This synopsis outlines the Japanese guideline Version 2.0 for the data acquisition protocol of oncology FDG-PET/CT scans that was created by a joint task force of the Japanese Society of Nuclear Medicine Technology, the Japanese Society of Nuclear Medicine and the Japanese Council of PET Imaging, and was published in Kakuigaku-Gijutsu 2013; 33:377-420 in Japanese. The guideline aims at standardizing the PET image quality among PET centers and different PET camera models by providing criteria for the IEC body phantom image quality as well as for the patient PET image quality based on the noise equivalent count (NEC), NEC density and liver signal-to-noise ratio, so that the appropriate scanning parameters can be determined for each PET camera. This Version 2.0 covers issues that were not focused on in Version 1.0, including the accuracy of the standardized uptake value (SUV), effect of body size together with adjustment of scanning duration, and time-of-flight (TOF) reconstruction technique. Version 2.0 also presents data acquired with new PET camera models that were not tested in Version 1.0. Reference values for physical indicators of phantom image quality have been updated as well.

Performance Evaluation of a New Dedicated Breast PET Scanner Using NEMA NU4-2008 Standards.

UNLABELLED: The aim of this work was to evaluate the performance characteristics of a newly developed dedicated breast PET scanner, according to National Electrical Manufacturers Association (NEMA) NU 4-2008 standards. METHODS: The dedicated breast PET scanner consists of 4 layers of a 32 × 32 lutetium oxyorthosilicate-based crystal array, a light guide, and a 64-channel position-sensitive photomultiplier tube. The size of a crystal element is 1.44 × 1.44 × 4.5 mm. The detector ring has a large solid angle with a 185-mm aperture and an axial coverage of 155.5 mm. The energy windows at depth of interaction for the first and second layers are 400-800 keV, and those at the third and fourth layers are 100-800 keV. A fixed timing window of 4.5 ns was used for all acquisitions. Spatial resolution, sensitivity, counting rate capabilities, and image quality were evaluated in accordance with NEMA NU 4-2008 standards. Human imaging was performed in addition to the evaluation. RESULTS: Radial, tangential, and axial spatial resolution measured as minimal full width at half maximum approached 1.6, 1.7, and 2.0 mm, respectively, for filtered backprojection reconstruction and 0.8, 0.8, and 0.8 mm, respectively, for dynamic row-action maximum-likelihood algorithm reconstruction. The peak absolute sensitivity of the system was 11.2%. Scatter fraction at the same acquisition settings was 30.1% for the rat-sized phantom. Peak noise-equivalent counting rate and peak true rate for the ratlike phantom was 374 kcps at 25 MBq and 603 kcps at 31 MBq, respectively. In the image-quality phantom study, recovery coefficients and uniformity were 0.04-0.82 and 1.9%, respectively, for standard reconstruction mode and 0.09-0.97 and 4.5%, respectively, for enhanced-resolution mode. Human imaging provided high-contrast images with restricted background noise for standard reconstruction mode and high-resolution images for enhanced-resolution mode. CONCLUSION: The dedicated breast PET scanner has excellent spatial resolution and high sensitivity. The performance of the dedicated breast PET scanner is considered to be reasonable enough to support its use in breast cancer imaging.

[Development of analysis software package for the two kinds of Japanese fluoro-d-glucose-positron emission tomography guideline].

Two kinds of Japanese guidelines for the data acquisition protocol of oncology fluoro-D-glucose-positron emission tomography (FDG-PET)/computed tomography (CT) scans were created by the joint task force of the Japanese Society of Nuclear Medicine Technology (JSNMT) and the Japanese Society of Nuclear Medicine (JSNM), and published in Kakuigaku-Gijutsu 27(5): 425-456, 2007 and 29(2): 195-235, 2009. These guidelines aim to standardize PET image quality among facilities and different PET/CT scanner models. The objective of this study was to develop a personal computer-based performance measurement and image quality processor for the two kinds of Japanese guidelines for oncology (18)F-FDG PET/CT scans. We call this software package the "PET quality control tool" (PETquact). Microsoft Corporation's Windows(™) is used as the operating system for PETquact, which requires 1070×720 image resolution and includes 12 different applications. The accuracy was examined for numerous applications of PETquact. For example, in the sensitivity application, the system sensitivity measurement results were equivalent when comparing two PET sinograms obtained from the PETquact and the report. PETquact is suited for analysis of the two kinds of Japanese guideline, and it shows excellent spec to performance measurements and image quality analysis. PETquact can be used at any facility if the software package is installed on a laptop computer.

Brain histamine H1 receptor occupancy of loratadine measured by positron emission topography: comparison of H1 receptor occupancy and proportional impairment ratio.

AIMS: We have evaluated the sedative properties of H1-antihistamines by using positron emission tomography (PET) and ¹¹C-doxepin. The purpose of the present study was to measure histamine H1 receptor occupancy (H1RO) of loratadine 10 mg in patients with allergic rhinitis and to compare this occupancy with that of d-chlorpheniramine 2 mg, a first-generation antihistamine. We also compared our PET findings with the proportional impairment ratio reported by McDonald et al. METHODS: The H1RO of loratadine 10 mg and d-chlorpheniramine 2 mg were evaluated in human brains in a double-blind and crossover design using ¹¹C-doxepin PET. Eleven young male patients with allergic rhinitis were examined by PET following oral single administration of loratadine 10 mg and d-chlorpheniramine 2 mg. RESULTS: Loratadine 10 mg occupied 11.7 ± 19.5% of histamine H1 receptors in the cortex, whereas d-chlorpheniramine 2 mg occupied 53.0 ± 33.2% in the same area, suggesting a non-sedating property of loratadine at a dose of 10 mg. The H1RO values of loratadine and d-chlorpheniramine as well as those of previous studies were found to be significantly proportional to the proportional impairment ratio (r = 0.899). CONCLUSION: Measurement of H1RO is a sensitive and absolute method to characterize the non-sedating property of drugs with H1 antagonistic activity.

Japanese guideline for the oncology FDG-PET/CT data acquisition protocol: synopsis of Version 1.0.

This synopsis outlines the Japanese guideline Version 1.0 for the data acquisition protocol of oncology FDG-PET/CT scans that was created by a joint task force of the Japanese Society of Nuclear Medicine Technology (JSNMT) and the Japanese Council of PET Imaging, and published in Kakuigaku-Gijutsu 29(2):195-235, 2009, in Japanese. The guideline aims at standardizing the PET image quality among facilities and different PET/CT scanner models by determining and/or evaluating the data acquisition condition in experiments using an IEC body phantom, as well as by proposing the criteria for human image quality evaluation using patient noise equivalent count (NEC), NEC density, and liver signal-to-noise ratio.

Significance of chronic marked hyperglycemia on FDG-PET: is it really problematic for clinical oncologic imaging?

OBJECTIVES: The purpose of this study was to evaluate the adverse effects of chronic marked hyperglycemia on clinical diagnostic performance of positron emission tomography (PET) using (18)F-fuorodeoxyglucose (FDG). METHODS: Fifty-seven scans of 54 patients, who received FDG-PET for the diagnosis of various cancer(s), and who showed high plasma glucose level of more than 200 mg/dl at the time of administration of FDG in spite of at least 4-h fasting, were retrospectively analyzed. In the clinical follow-up, this high plasma glucose was confirmed as chronic hyperglycemia derived from uncontrolled diabetes (n = 32) and untreated diabetes (n = 25). Based on the final diagnosis of malignancy obtained by histopathology or clinical follow-up for at least 6 months, the diagnostic performance of visual PET analysis was evaluated. RESULTS: Excluding nine scans of nine patients without sufficient follow-up, final diagnosis was obtained in 48 scans of 45 patients. In 36 scans of 36 patients, at least one malignant lesion was finally confirmed, and true-positive and false-negative results were obtained in 30 and six cases, respectively. Six cases showed false-negative results due to low FDG-avid pathological characteristics (hepatocellular carcinoma, etc.), chemotherapeutic effect or small tumor size. Overall, the patient-based sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were 83, 83, 94, 63 and 83%, respectively. In lesion-based diagnosis, 56 of 75 lesions (74%) were depicted by PET, while 19 lesions were negative on PET, also due to low FDG-avid characteristics or small size (less than 15 mm). CONCLUSIONS: At the time of chronic hyperglycemia (not acute hyperglycemia), the adverse effect caused by high plasma glucose level was minimum. The FDG uptake of the tumor maintained a sufficiently high level for visual clinical diagnosis in most cases, except in the cases of low FDG-avid tumors or small lesions (15 mm in size).

Cerebral histamine H1 receptor binding potential measured with PET under a test dose of olopatadine, an antihistamine, is reduced after repeated administration of olopatadine.

UNLABELLED: Some antihistamine drugs that are used for rhinitis and pollinosis have a sedative effect as they enter the brain and block the H(1) receptor, potentially causing serious accidents. Receptor occupancy has been measured with PET under single-dose administration in humans to classify antihistamines as more sedating or as less sedating (or nonsedating). In this study, the effect of repeated administration of olopatadine, an antihistamine, on the cerebral H(1) receptor was measured with PET. METHODS: A total of 17 young men with rhinitis underwent dynamic brain PET with (11)C-doxepin at baseline, under an initial single dose of 5 mg of olopatadine (acute scan), and under another 5-mg dose after repeated administration of olopatadine at 10 mg/d for 4 wk (chronic scan). The H(1) receptor binding potential was estimated using Logan graphical analysis with cerebellum as reference region input. RESULTS: The acute scan showed a slight decrease in H(1) receptor binding potential across the cerebral cortex (by 15% in the frontal cortex), but the chronic scan showed a marked decrease (by 45% from the acute scan in the frontal cortex). Behavioral data before and after the PET scans did not reveal any sedative effect. CONCLUSION: The results may be interpreted as either intracerebral accumulation of olopatadine or H(1) receptor downregulation due to repeated administration. The study shows feasibility and potential value for PET in evaluating the pharmacologic effect of a drug not only after a single dose but also after repeated administration.