Impact of the size of the normal database on the performance of the specific binding ratio in dopamine transporter SPECT

Background: This study investigated the impact of the size of the normal database on the classification performance of the specific binding ratio (SBR) in dopamine transporter (DAT) SPECT with [123I]FP-CIT in different settings. Methods: The first subject sample comprised 645 subjects from the Parkinson's Progression Marker Initiative (PPMI), 207 healthy controls (HC), and 438 Parkinson's disease (PD) patients. The second sample comprised 372 patients from clinical routine patient care, 186 with non-neurodegenerative parkinsonian syndrome (PS) and 186 with neurodegenerative PS. Single-photon emission computed tomography (SPECT) images of the clinical sample were reconstructed with two different reconstruction algorithms (filtered backprojection, iterative ordered subsets expectation maximization (OSEM) reconstruction with resolution recovery). The putaminal specific binding ratio (SBR) was computed using an anatomical region of interest (ROI) predefined in standard (MNI) space in the Automated Anatomic Labeling (AAL) atlas or using hottest voxels (HV) analysis in large predefined ROIs. SBR values were transformed to z-scores using mean and standard deviation of the SBR in a normal database of varying sizes (n = 5, 10, 15,…, 50) randomly selected from the HC subjects (PPMI sample) or the patients with non-neurodegenerative PS (clinical sample). Accuracy, sensitivity, and specificity for identifying patients with PD or neurodegenerative PS were determined as performance measures using a predefined fixed cutoff on the z-score. This was repeated for 10,000 randomly selected normal databases, separately for each size of the normal database. Mean and 5th percentile of the performance measures over the 10,000 realizations were computed. Accuracy, sensitivity, and specificity when using the whole set of HC or non-neurodegenerative PS subjects as normal database were used as benchmark. Results: Mean loss of accuracy of the putamen SBR z-score was below 1% when the normal database included at least 15 subjects, independent of subject sample (PPMI or clinical), reconstruction method (filtered backprojection or OSEM), and ROI method (AAL or HV). However, the variability of the accuracy of the putamen SBR z-score decreased monotonically with increasing size of normal database and was still considerable at size 15. In order to achieve less than 5% "maximum" loss of accuracy (defined by the 5th percentile) in all settings required at least 25 to 30 subjects in the normal database. Reduction of mean and "maximum" loss of accuracy of the putamen SBR z-score by further increasing the size of the normal database was very small beyond size 40. Conclusions: The results of this study suggest that 25 to 30 is the minimum size of the normal database to reliably achieve good performance of semi-quantitative analysis in dopamine transporter (DAT) SPECT, independent of the algorithm used for image reconstruction and the ROI method used to estimate the putaminal SBR

Correction for continuous motion in small animal PET

In small animal PET imaging experiments, animals are generally required to be anaesthetized to avoid motion artifacts. However, anaesthesia can alter biochemical pathways within the brain, thus affecting the physiological parameters under investigation. The ability to image conscious animals would overcome this problem andopen up the possibility of entirely new investigational paradigms.We have previously reported a motion-correction approach for small animal PET imaging that employs motion tracking and line of response (LOR) rebinning, and successfully demonstrated its use in phantom scans with step wise motion. In this paper we investigate an improvedsynchronization method in which TTL signals output by the motion tracker are sent to the microPET gate input to trigger the insertion of gate marks in the list mode stream that indicate the times of motion tracker measurements. The method is tested in separate microPET scans of a phantom and an anaesthetized rat which were moved continuously during data acquisition. In both cases, the motion-corrected images corresponded well with the motion-free images.We also tested the effect of pose measurement rate and synchronization error on motion correction accuracy by down-sampling and temporally misaligning list mode and motion data in a phantom study. Motion correction errors were relatively large at frequencies below -10Hz and fell rapidly to a roughly constant level above 20Hz. Motion correction errors also increased rapidly with increasingsynchronization error. In practice the acceptable limits of sampling rate and synchronization error will depend on the velocity of the motion. Using the synchronization technique presented here, and an adequate pose sampling rate, it was possible to correct for continuous motion similar to that we expect to be exhibited by conscious rats during microPET imaging experiments

Evaluation of transmission methodology and attenuation correction for the microPET Focus 220 animal scanner

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Performance evaluation of a novel multi-pinhole collimator for dopamine transporter SPECT

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Whole-body biodistribution and radiation dosimetry of [18F]PR04.MZ: a new PET radiotracer for clinical management of patients with movement disorders

Purpose [18F]PR04.MZ is a new PET imaging agent for dopamine transporters, providing excellent image quality and allowing for the evaluation of patients with movement disorders such as Parkinson’s disease. The objective of this study was to evaluate the biodistribution and radiation dosimetry of [18F]PR04.MZ by serial PET imaging. Methods Six healthy subjects (n = 3 males, n = 3 females) were enrolled in this study. A series of 14 whole-body PET/CT scans were acquired until 5.5 h post-injection of 200 ± 11 MBq of [18F]PR04.MZ. After rigid co-registration, volumes of interest were outlined either on CT or PET images. Time-integrated activity coefficients were calculated for selected source organs. Organ absorbed doses, and the effective dose were calculated using IDAC-Dose 2.1. Results Physiological uptake of [18F]PR04.MZ was mainly observed in the striatum, brain, liver, gall bladder, intestine, red marrow and cortical bone. [18F]PR04.MZ was primarily excreted via hepatobiliary clearance and, to a lower extent, via renal clearance. The normalized absorbed doses were highest in gall bladder wall (32.2 ± 6.4 µGy/MBq), urinary bladder wall (27.2 ± 4.5 µGy/MBq), red marrow (26.5 ± 1.4 µGy/MBq), cortical bone surface (26.3 ± 2.5 µGy/MBq), liver (22.5 ± 1.8 µGy/MBq) and kidneys (21.8 ± 1.1 µGy/MBq). The effective dose according to ICRP 60 and 103 was 16.3 ± 1.1 and 16.6 ± 1.5 µSv/MBq, respectively. Conclusion [18F]PR04.MZ has a favourable dosimetry profile, comparable to those of other 18F-labelled PET tracers, and is suitable for larger clinical applications. Trial registration CEC SSM Oriente, Santiago, Chile, permit 20140520

Development and dosimetry of Pb-203 / Pb-212 labeled PSMA ligands – Bringing “the Lead” into PSMA-Targeting Alpha Therapy?

The development of a prostate-specific membrane antigen (PSMA)-ligand for labeling with different radioisotopes of lead and the approximation of the dosimetry of a simulated Pb-212 based alpha-therapy by using its Pb-203 imaging analogue.JRC.G.I.5-Advanced Nuclear Knowledg

Investigation of motion-corrected VOI reconstruction for freely moving small animals with microPET

We are developing an imaging system that enables the brain of a freely moving animal to be imaged with microPET while simultaneously observing its behaviour. Towards this end, we investigated the feasibility of reconstructing a motion-tracked volume of interest (VOI) in the presence of an extraneous activity compartment with unknown motion. A dual phantom study was performed to simulate movements of a freely moving animal. Both phantoms were moved through discrete positions but only one phantom (representing the head) was tracked. The multiple acquisition frames (MAF) and LOR rebinning methods were applied based on the measured motion of the tracked phantom. We also investigated alternative approaches that are hybrids of these two methods. We found that LOR rebinning causes up to 90% ‘lost events’ (events that would have been measured had motion not occurred) when applied to a freely moving target and this fraction can be significantly reduced using the hybrid approaches, resulting in improved image quality. The MAF-based motion correction yields good results but is not practical for unconstrained motion due to the assumption of no motion within each time segment. We conclude that it is feasible to reconstruct a target VOI in the presence of extraneous activity whose motion is unknown, provided the target motion is accurately tracked

Development and dosimetry of 203Pb/212Pb-labelled PSMA ligands: bringing “the lead” into PSMA-targeted alpha therapy?

Purpose: The development of a prostate-specific membrane antigen (PSMA)-ligand for labeling with different isotopes of lead and the approximation of the dosimetry of a simulated 212Pb-based alpha-therapy by using its 203Pb imaging analogue. Methods: Four novel Glu-urea-based ligands containing the chelators p-SCN-Bn-TCMC or DO3AM were synthesized. Affinity and internalization were studied in C4-2 cells, biodistribution in C4-2 tumor bearing mice. The most promising compound 203Pb-CA012 was translated to clinical application. Two patients underwent planar scintigraphy scans at 0.4 h, 4 h, 18 h, 28 h and 42 h post-injection, accompanied with urine and blood-sampling. The time-activity-curves of source organs were extrapolated from 203Pb to 212Pb and the calculated residence times of 212Pb were forwarded to its unstable daughter nuclides. QDOSE and OLINDA were used for dosimetry calculations. Results: All the ligands possess low nanomolar affinities towards PSMA. The compounds CA09 and CA012 additionally showed specific ligand-induced internalization up to 27.37 ± 2.37 and 15.63 ± 2.06 percent of the injected activity, respectively. The radiolabeled 203Pb-PSMA ligands were stable in serum for 72 h. Small animal imaging and organ distribution analysis of CA012 revealed high specific uptake in the tumor tissue when compared to other organs. This compound also showed a rapid clearance from the kidneys 5.1 ± 2.5 at 1 h to 0.9 ± 0.1 %ID/g at 24 h. In patients an effective dose of approximately 6-7 mSv was estimated for 250-300 MBq of diagnostic 203Pb-CA012. Assuming instant decay of daughter nuclides, a therapeutic activity of 100 MBq of 212Pb-CA012 is projected to equivalent doses of 0.6 SvRBE5 for red-marrow, 4.3 SvRBE5 for salivary glands, 4.9 SvRBE5 for kidneys, 0.7 SvRBE5 for liver and 0.2 SvRBE5 for other organs; representative tumor lesions averaged 13.2 SvRBE5. Conclusion: The ligands CA009 and CA012 are promising agents to target PSMA with various isotopes of lead. According to its projected patient dosimetry 212Pb-CA012 is a potential candidate for PSMA-targeting alpha-therapy. The dosimetry estimate of radiopharmaceuticals decaying with the release of instable daughter nuclides has some inherent limitations, thus clinical translation should be done cautiously. Once 212Pb becomes more broadly available, further evaluation is warranted.  JRC.G.I.5-Advanced Nuclear Knowledg