Whole-body biodistribution and the influence of body activity on brain kinetic analysis of the 11C-PiB PET scan.

Dynamic 11C-PiB PET imaging with kinetic analysis has been performed for accurate quantification of amyloid binding in patients with Alzheimer's disease (AD). In this study, we measured the whole-body biodistribution of 11C-PiB in nine subjects. We then evaluated the effect of body activity on quantitative accuracy of brain 11C-PiB three-dimensional (3D) dynamic PET. Based on clinical biodistribution data, we conducted phantom experiments to estimate the effect of body activity on quantification of the brain 3D dynamic 11C-PiB PET data and the error introduced by body activity using six different PET camera models. One of the PET cameras was used to acquire 11C-PiB brain 3D dynamic PET data on a patient with AD. We calculated the distribution volume ratio (DVR) in two kinetic methods using both the original human time-activity-curve (TAC) data and the TAC corrected for the error caused by body activity. In the early phase, both healthy subjects and patients with AD showed a biodistribution of 11C-PiB that reflected regional blood flow. In the simulated early phase of the phantom experiments, activity outside the field of view led to a maximum 6.0% overestimation of brain activity in the vertex region. Conversely, the effect of body activity on the DVR estimate was small (≤1.2%), probably because the tested kinetic methods did not rely heavily on early phase data. These results indicate that the effect of body activity on brain 11C-PiB PET quantification is generally small and that it depends on the method of kinetic analysis, the region of interest, and the PET camera model used.

Inter-rater variability of visual interpretation and comparison with quantitative evaluation of 11C-PiB PET amyloid images of the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) multicenter study.

PURPOSE: The aim of this study was to assess the inter-rater variability of the visual interpretation of 11C-PiB PET images regarding the positivity/negativity of amyloid deposition that were obtained in a multicenter clinical research project, Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI). The results of visual interpretation were also compared with a semi-automatic quantitative analysis using mean cortical standardized uptake value ratio to the cerebellar cortex (mcSUVR). METHODS: A total of 162 11C-PiB PET scans, including 45 mild Alzheimer's disease, 60 mild cognitive impairment, and 57 normal cognitive control cases that had been acquired as J-ADNI baseline scans were analyzed. Based on visual interpretation by three independent raters followed by consensus read, each case was classified into positive, equivocal, and negative deposition (ternary criteria) and further dichotomized by merging the former two (binary criteria). RESULTS: Complete agreement of visual interpretation by the three raters was observed for 91.3% of the cases (Cohen κ = 0.88 on average) in ternary criteria and for 92.3% (κ = 0.89) in binary criteria. Cases that were interpreted as visually positive in the consensus read showed significantly higher mcSUVR than those visually negative (2.21 ± 0.37 vs. 1.27 ± 0.09, p < 0.001), and positive or negative decision by visual interpretation was dichotomized by a cut-off value of mcSUVR = 1.5. Significant positive/negative associations were observed between mcSUVR and the number of raters who evaluated as positive (ρ = 0.87, p < 0.0001) and negative (ρ = -0.85, p < 0.0001) interpretation. Cases of disagreement among raters showed generally low mcSUVR. CONCLUSIONS: Inter-rater agreement was almost perfect in 11C-PiB PET scans. Positive or negative decision by visual interpretation was dichotomized by a cut-off value of mcSUVR = 1.5. As some cases of disagreement among raters tended to show low mcSUVR, referring to quantitative method may facilitate correct diagnosis when evaluating images of low amyloid deposition.

Phantom criteria for qualification of brain FDG and amyloid PET across different cameras.

BACKGROUND: While fluorodeoxyglucose (FDG) and amyloid PET is valuable for patient management, research, and clinical trial of therapeutics on Alzheimer's disease, the specific details of the PET scanning method including the PET camera model type influence the image quality, which may further affect the interpretation of images and quantitative capabilities. To make multicenter PET data reliable and to establish PET scanning as a universal diagnostic technique and a verified biomarker, we have proposed phantom test procedures and criteria for optimizing image quality across different PET cameras. RESULTS: As the method, four physical parameters (resolution, gray-white contrast, uniformity, and image noise) were selected as essential to image quality for brain FDG and amyloid PET and were measured with a Hoffman 3D brain phantom and a uniform cylindrical phantom on a total of 12 currently used PET models. The phantom radioactivity and acquisition time were determined based on the standard scanning protocol for each PET drug (FDG, 11C-PiB, 18F-florbetapir, and 18F-flutemetamol). Reconstruction parameters were either determined based on the methods adopted in ADNI, J-ADNI, and other research and clinical trials or optimized based on measured phantom image parameters under various reconstruction conditions. As the result, phantom test criteria were proposed as follows: (i) 8 mm FWHM or better resolution and (ii) gray/white %contrast ≥55 % with the Hoffman 3D brain phantom and (iii) SD of 51 small region of interests (ROIs) ≤0.0249 (equivalent to 5 % variation) for uniformity and (iv) image noise (SD/mean) ≤15 % for a large ROI with the uniform cylindrical phantom. These criteria provided image quality conforming to those multicenter clinical studies and were also achievable with most of the PET cameras that are currently used. CONCLUSIONS: The proposed phantom test criteria facilitate standardization and qualification of brain FDG and amyloid PET images and deserve further evaluation by future multicenter clinical studies.

Exploratory human PET study of the effectiveness of (11)C-ketoprofen methyl ester, a potential biomarker of neuroinflammatory processes in Alzheimer's disease.

INTRODUCTION: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD). As a biomarker of neuroinflammatory processes, we designed (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) to increase the blood-brain barrier permeability of ketoprofen (KTP), a selective cyclooxygenase-1 (COX-1) inhibitor. Animal studies indicated that [(11)C]KTP-Me enters the brain and accumulates in activated microglia of inflammatory lesions. In a first-in-human study, we reported that [(11)C]KTP-Me is a safe positron emission tomography (PET) tracer and enters the brain; the radioactivity is washed out from normal cerebral tissue. Here we explored the efficacy of [(11)C]KTP-Me as a diagnostic biomarker of neuroinflammatory processes in AD. METHODS: [(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor. Nine subjects (four healthy subjects, two Pittsburgh compound-B (PiB)-positive patients with mild cognitive impairment (MCI), and three PiB-positive AD patients) underwent a dynamic brain PET scan for 70min after injection. We evaluated differences in cortical retention and washout rate in the brain between healthy subjects and MCI/AD patients. RESULTS: A brain distribution pattern reflecting blood flow in the early-phase image was seen in both healthy subjects and MCI/AD patients. Cortical activity gradually cleared in all groups. However, we observed no obvious difference in the washout rate between healthy subjects and MCI/AD patients or between MCI and AD patients. CONCLUSIONS: [(11)C]KTP-Me cannot be useful as a potential diagnostic biomarker for MCI/AD. Further improvements in binding affinity and specificity, etc., are needed to be a diagnostic biomarker of neuroinflammation in AD. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: [(11)C]KTP-Me is a new tracer that targets COX-1. [(11)C]KTP-Me is expected to be a diagnostic biomarker of neuroinflammation in AD in the future. The effectiveness was limited in a small number of AD patients. Therefore, further studies are needed to clarify the usefulness of [(11)C]KTP-Me.

Optimization of image reconstruction conditions with phantoms for brain FDG and amyloid PET imaging.

OBJECTIVES: The purpose of this study was to optimize image reconstruction conditions for brain (18)F-FDG, (11)C-PiB, (18)F-florbetapir and (18)F-flutemetamol PET imaging with Discovery-690 PET/CT for diagnosis and research on Alzheimer's disease (AD) based on the standard imaging protocols and phantom test procedures and criteria published by the Japanese society of nuclear medicine (JSNM). METHODS: A Hoffman 3D brain phantom and a cylindrical pool phantom were scanned according to the JSNM procedure, and the reconstruction conditions (iteration, subset, post-filter) were optimized so that the images satisfy the JSNM criteria regarding spatial resolution (FWHM ≤ 8 mm) and gray/white matter contrast (%contrast ≥ 55%) on the Hoffman phantom and uniformity (SD of small ROIs ≤ 0.0249) and image noise (coefficient of variation ≤ 15 %) on the pool phantom. Human images were acquired with (18)F-FDG (15-min scan starting at 30 min post-injection [p.i.] of 185 MBq), (11)C-PiB (20-min scan starting at 50 min p.i. of 555 MBq), (18)F-florbetapir (10-min scan starting at 50 min p.i. of 370 MBq) and (18)F-flutemetamol (30-min scan starting at 90 min p.i. of 185 MBq) on 1 or 2 subjects for each tracer and reconstructed with thus determined conditions to evaluate the image quality visually. The effect of reconstruction parameters on the standardized uptake value ratio (SUVR) was also evaluated on 5 amyloid-positive and 5 amyloid-negative PiB images. RESULTS: A sufficient image quality was obtained at an iterative update (product of iteration and subset) of 64 for (18)F-FDG. The same reconstruction parameters with an additional Gaussian filter of 5 mm FWHM was optimal for (11)C-PiB, (18)F-florbetapir and (18)F-flutemetamol to achieve the phantom criteria. Those optimal reconstruction conditions were confirmed with human images. The SUVR value was stable over a wide range of iterative updates around the optimal parameters both for positive and negative amyloid images. CONCLUSIONS: Optimal image reconstruction conditions were determined for brain (18)F-FDG and amyloid PET imaging with Discovery-690 PET/CT for diagnosis and research on AD based on the JSNM phantom criteria. This supports feasibility of the phantom criteria for standardization and harmonization of brain (18)F-FDG and amyloid PET for multicenter studies.

[Harmonization of Standardized Uptake Value among Different Generation PET/ CT Cameras Based on a Phantom Experiment -Utility of SUV(peak)].

Standardized uptake value (SUV) has been widely used as a semi-quantitative metric of uptake in FDGPET/ CT for diagnosis of malignant tumors and evaluation of tumor therapies. However, the SUV depends on various factors including PET/CT scanner specifications and reconstruction parameters. The purpose of this study is to harmonize the SUV among two PET/CT models of different generation: two units of Discovery ST Elite Performance(DSTEP) and Discovery 690 (D690) PET/CT scanners. The NEMA body phantom filled with 18F solution was scanned for 30 minutes in list-mode. The D690 PET images were reconstructed with OSEM, OSEM+TOF, and OSEM+PSF. Gaussian post-filters of 4-9 mm FWHM were applied to find the parameters that provides harmonized SUV. We determined the SUV-harmonized parameter for each reconstruction algorithm. Then, the 10 PET images simulating clinical scan conditions were respectively generated to evaluate the bias and variability of SUV(max) and SUV(peak). The SUV(max) strongly depended not only on spatial resolution but also on image noise. On the other hand, the SUV(peak) was a robust metric to image noise level. TOF improved the variability of SUV(max) and SUV(peak). Thus, we were able to harmonize the spatial resolution using SUV(peak) based on the phantom study. Because SUV(max) was also strongly affected by image noise, sufficient count statistics is essential for SUV(max) harmonization. We recommended that TOF reconstruction and SUV(peak) metric should be used to harmonize SUV.

Influence of Statistical Fluctuation on Reproducibility and Accuracy of SUVmax and SUVpeak: A Phantom Study.

UNLABELLED: Standardized uptake values (SUVs) have been widely used in the diagnosis of malignant tumors and in clinical trials of tumor therapies as semiquantitative metrics of tumor (18)F-FDG uptake. However, SUVs for small lesions are liable to errors due to partial-volume effect and statistical noise. The purpose of this study was to evaluate the reproducibility and accuracy of maximum and peak SUV (SUVmax and SUVpeak, respectively) of small lesions in phantom experiments. METHODS: We used a body phantom with 6 spheres in a quarter warm background. The PET data were acquired for 1,800 s in list-mode, from which data were extracted to generate 15 PET images for each of the 60-, 90-, 120-, 150-, and 180-s scanning times. The SUVmax and SUVpeak of the hot spheres in the 1,800-s scan were used as a reference (SUVref,max and SUVref,peak). Coefficients of variation for both SUVmax and SUVpeak in hot spheres (CVmax and CVpeak) were calculated to evaluate the variability of the SUVs. On the other hand, percentage differences between SUVmax and SUVref,max and between SUVpeak and SUVref,peak were calculated for evaluation of the accuracy of SUV. We additionally examined the coefficients of variation of background activity and the percentage background variability as parameters for the physical assessment of image quality. RESULTS: Visibility of a 10-mm-diameter hot sphere was considerably different among scan frames. The CVmax and CVpeak increased as the sphere size became smaller and as the acquisition time became shorter. SUVmax was generally overestimated as the scan time shortened and the sphere size increased. The SUVmax and SUVpeak of a 37-mm-diameter sphere for 60-s scans had average positive biases of 28.3% and 4.4%, compared with the reference. CONCLUSION: SUVmax was variable and overestimated as the scan time decreased and the sphere size increased. In contrast, SUVpeak was a more robust and accurate metric than SUVmax. The measurements of SUVpeak (or SUVpeak normalized to lean body mass) in addition to SUVmax are desirable for reproducible and accurate quantification in clinical situations.

Human whole-body biodistribution and dosimetry of a new PET tracer, [(11)C]ketoprofen methyl ester, for imagings of neuroinflammation.

INTRODUCTION: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease and other brain disorders, and nonsteroidal anti-inflammatory drugs (NSAIDs) are considered therapeutic candidates. As a biomarker of neuroinflammatory processes, (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) was designed to allow cerebral penetration of ketoprofen (KTP), an active form of a selective cyclooxygenase-1 inhibitor that acts as an NSAID. Rat neuroinflammation models indicate that [(11)C]KTP-Me enters the brain and is retained in inflammatory lesions, accumulating in activated microglia. [(11)C]KTP-Me is washed out from normal tissues, leading to the present first-in-human exploratory study. METHODS: [(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor, purified with high-performance liquid chromatography, and prepared as an injectable solution including PEG400, providing radiochemical purity of >99% and specific activity of >25GBq/µmol at injection. Six young healthy male humans were injected with [(11)C]KTP-Me and scanned with PET camera to determine the early-phase brain time course followed by three whole-body scans starting 8, 20, and 40 min post-injection, together with sequential blood sampling and labeled metabolite analysis. RESULTS: No adverse effects were observed during PET scanning after [(11)C]KTP-Me injection. [(11)C]KTP-Me was rapidly metabolized to (11)C-labeled ketoprofen ([(11)C]KTP) within 2-3 min and was gradually cleared from blood. The radioactivity entered the brain with an average peak cortical SUV of 1.5 at 2 min. The cortical activity was gradually washed out. Whole-body images indicated that the urinary bladder was the major excretory pathway. The organ with the highest radiation dose was the urinary bladder (average dose of 41µGy/MBq, respectively). The mean effective dose was 4.7µSv/MBq, which was comparable to other (11)C-labeled radiopharmaceuticals. CONCLUSION: [(11)C]KTP-Me demonstrated a favorable dosimetry, biodistribution, and safety profile. [(11)C]KTP-Me entered the human brain, and the radioactivity was washed out from cerebral tissue. These data warrant further exploratory studies on patients with neuroinflammation.

Equal sensitivity of early and late scans after injection of FDG for the detection of Alzheimer pattern: an analysis of 3D PET data from J-ADNI, a multi-center study.

OBJECTIVE: To determine the optimal accumulation time for three-dimensional positron emission tomography (3D-PET) with (18)F-2-fluoro-2-deoxy-D-glucose ((18)F-FDG) to detect the brain uptake pattern typical of Alzheimer's disease (AD). METHODS: Patients with mild AD or amnestic mild cognitive impairment (MCI) and normal control subjects were recruited in the Japanese Alzheimer's disease neuroimaging initiative and examined with a PET scan during the 30-60 min after FDG injection. Three independent blinded experts interpreted the 30- to 60-min sum images, and images of patients with AD and MCI presenting AD patterns and normal subjects presenting normal patterns were used in the analysis. Early-scan (ES) and late-scan (LS) images were obtained from the data acquired at 30-35 min and 55-60 min after the injection, respectively. Separate target regions of interest (ROI) for ES and LS were defined as areas of significant reductions in the posterior cingulate and parietotemporal lobe in both hemispheres from the results of an initial cohort with 21 patients (AD 16, MCI 5) and 19 controls. A subsequent sample of 36 (AD 9, MCI 27) patients and 38 controls were used to compare the diagnostic capability of ES and LS using Z scores within the target ROI in individual statistical parametric mapping analysis. RESULTS: Compared to LS, ES showed lower activity in the frontal lobes and higher activity in the venous sinus than LS; however, the diagnostic capability of ES and LS did not significantly differ (sensitivity 0.97 and 0.97, specificity 0.82 and 0.84, area under the receiver-operating characteristic curve 0.96 and 0.97, respectively). CONCLUSIONS: For a qualitative diagnosis of the AD pattern in 3D FDG-PET, results of ES were equivalent to those of LS. ES may be an option to shorten the entire PET procedure time, particularly in diagnosing early stages of AD.

[Multi-center study of inter-scanner difference in brain positron emission tomography].

We showed scanner dependence of brain (18)F-FDG and (11)C-PiB images by using phantom examination with nine kinds of positron emission tomography (PET) scanners. We used two types of phantoms, cylindrical phantom with 15 cm inside diameter and three-dimensional (3D) brain phantom, and we set the body phantom on the bed to examine the effect of scatter and random coefficients from outside of the axial field of view (AFOV). Radioactivity and distance of the two phantoms were determined by a pilot study to obtain a condition similar to the clinical study. Axial uniformity was evaluated by circular region of interest (ROI) of 12 cm diameter, set in the center of the reconstruction image of the cylindrical phantom. As a result, the standardized uptake value (SUV) was lower than the true value in some scanners, and there was a scanner in which the axial uniformity was deteriorated by high radioactivity outside the AFOV. In the cylindrical phantom, the axial uniformity of the scanner was improved using the new dead-time correction method; however, it was not improved in the 3D brain phantom. Quality-controlled PET scanners are important to maintain constant levels for multicenter studies.

Head motion evaluation and correction for PET scans with 18F-FDG in the Japanese Alzheimer's disease neuroimaging initiative (J-ADNI) multi-center study.

OBJECTIVE: Head motion during 30-min (six 5-min frames) brain PET scans starting 30 min post-injection of FDG was evaluated together with the effect of post hoc motion correction between frames in J-ADNI multicenter study carried out in 24 PET centers on a total of 172 subjects consisting of 81 normal subjects, 55 mild cognitive impairment (MCI) and 36 mild Alzheimer's disease (AD) patients. METHODS: Based on the magnitude of the between-frame co-registration parameters, the scans were classified into six levels (A-F) of motion degree. The effect of motion and its correction was evaluated using between-frame variation of the regional FDG uptake values on ROIs placed over cerebral cortical areas. RESULT: Although AD patients tended to present larger motion (motion level E or F in 22 % of the subjects) than MCI (3 %) and normal (4 %) subjects, unignorable motion was observed in a small number of subjects in the latter groups as well. The between-frame coefficient of variation (SD/mean) was 0.5 % in the frontal, 0.6 % in the parietal and 1.8 % in the posterior cingulate ROI for the scans of motion level 1. The respective values were 1.5, 1.4, and 3.6 % for the scans of motion level F, but reduced by the motion correction to 0.5, 0.4 and 0.8 %, respectively. The motion correction changed the ROI value for the posterior cingulate cortex by 11.6 % in the case of severest motion. CONCLUSION: Substantial head motion occurs in a fraction of subjects in a multicenter setup which includes PET centers lacking sufficient experience in imaging demented patients. A simple frame-by-frame co-registration technique that can be applied to any PET camera model is effective in correcting for motion and improving quantitative capability.

[Abnormal bone marrow uptake of 99mTc-tetrofosmin in myelodysplastic syndrome with ineffective hematopoiesis: a case report].

Eighty-four-year-old male patient with liver cirrhosis, suffered from dyspnea on August 2006. Four months later, his symptom has remained and he was admitted to our hospital. A white blood cell decrease and anemia were observed by the blood test. He underwent echocardiography and 99mTc-tetrofosmin myocardial scintigraphy (99mTc-Tf) at rest, which showed no abnormal cardiac imaging. But 99mTc-Tf whole-body planar imaging showed extremely increased bone marrow uptake. 99mTc-HMDP bone scintigraphy also showed abnormal hot spots in the same skeletal regions. Bone marrow biopsy revealed myelodysplastic syndrome like findings. 201Tl and 99mTc as tracers for myocardial perfusion imagings were used to evaluate coronary heart disease, but increased uptake of these tracers were reported in malignant tumors and bone metastasis. He did not have malignant tumor or bone metastasis, so increased uptake of 99mTc-Tf and 99mTc-HMDP was thought to be caused by hyperactive flow with ineffective hematopoiesis. We report a case that abnormal skeletal uptake of 99mTc-Tf which was caused by ineffective hematopoiesis of myelodysplastic syndrome.