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Purpose: Positron emission tomography (PET) imaging of mutant huntingtin (mHTT) aggregates is a potential tool to monitor disease progression as well as the efficacy of candidate therapeutic interventions for Huntington's disease (HD). To date, the focus has been mainly on the investigation of 11 C radioligands; however, favourable 18 F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [ 18 F]CHDI-650 PET radiotracer using a combination of in vivo and in vitro approaches in a mouse model of HD., Methods: After characterising [ 18 F]CHDI-650 using in vitro autoradiography, we assessed in vivo plasma and brain radiotracer stability as well as kinetics through dynamic PET imaging in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 months of age. Additionally, we performed a head-to-head comparison study at 3 months with the previously published [ 11 C]CHDI-180R radioligand., Results: Plasma and brain radiometabolite profiles indicated a suitable metabolic profile for in vivo imaging of [ 18 F]CHDI-650. Both in vitro autoradiography and in vivo [ 18 F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p < 0.0001) despite the poor test-retest reliability. [ 18 F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [ 11 C]CHDI-180R., Conclusion: Overall, [ 18 F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [ 18 F]CHDI-650 represents the first suitable 18 F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway., Competing Interests: Declarations. Ethics approval: Experiments followed the European Committee (decree 2010/63/CEE) and were approved by the Ethical Committee for Animal Testing (ECD 2019–39) at the University of Antwerp (Belgium). Conflict of interests: IMS, CD, VK, JB, and LL are employed by CHDI Management, Inc. the company that manages the scientific activities of CHDI Foundation, Inc. No other potential conflicts of interest relevant to this article exist., (© 2024. The Author(s).)

To prevent motion artifacts in small animal positron emission tomography (PET), animals are routinely scanned under anesthesia or physical restraint. Both may potentially alter metabolism and neurochemistry. This study investigates the feasibility of fully awake acquisition and subsequent absolute quantification of dynamic brain PET data via pharmacokinetic modelling in moving rats using the glutamate 5 receptor radioligand [ 11 C]ABP688 and point source based motion correction. Five male rats underwent three dynamic [ 11 C]ABP688 PET scans: two test-retest awake PET scans and one scan under anesthesia for comparison. Specific radioligand binding was determined via the simplified reference tissue model (reference: cerebellum) and outcome parameters BP ND and R 1 were evaluated in terms of stability and reproducibility. Test-retest measurements in awake animals gave reliable results with high correlations of BP ND (y = 1.08 × -0.2, r = 0.99, p < 0.01) and an acceptable variability (mean over all investigated regions 15.7 ± 2.4%). Regional [ 11 C]ABP688 BP ND s under awake and anesthetized conditions were comparable although in awake scans, absolute radioactive peak uptakes were lower and relative blood flow in terms of R 1 was higher. Awake small animal PET with absolute quantification of neuroreceptor availability is technically feasible and reproducible thereby providing a suitable alternative whenever effects of anesthesia are undesirable, e.g. in sleep research., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:Alexander Drzezga: Research support: Siemens Healthineers, Life Molecular Imaging, GE Healthcare, AVID Radiopharmaceuticals, Sofie, Eisai, Novartis/AAA, Ariceum TherapeuticsSpeaker Honorary/Advisory Boards: Siemens Healthineers, Sanofi, GE Healthcare, Biogen, Novo Nordisk, Invicro, Novartis/AAA, Bayer VitalStock: Siemens Healthineers, Lantheus Holding, Structured therapeutics, ImmunoGenPatents: Patent for 18 F-JK-PSMA- 7 (Patent No.: EP3765097A1; Date of patent: Jan. 20, 2021).

Since accurate quantification of 2-deoxy-2- 18 F-fluoro-D-glucose ([ 18 F]FDG) positron emission tomography (PET) requires dynamic acquisition with arterial input function, more practical semi-quantitative (static) approaches are often preferred. However, static standardized uptake values (SUV) are typically biased due to large variations in body weight (BW) occurring over time in animal studies. This study aims to improve static [ 18 F]FDG PET SUV quantification by better accounting for BW variations in rats. We performed dynamic [ 18 F]FDG PET imaging with arterial blood sampling in rats (n = 27) with different BW (range 0.230-0.487 kg). By regressing the area under the curve of the input function divided by injected activity against BW (r 2 =0.697), we determined a conversion factor f(BW) to be multiplied with SUV and SUV glc to obtain ratSUV and ratSUV glc , providing an improved estimate of the net influx rate K i (r = 0.758, p<0.0001) and cerebral metabolic rate of glucose MR glc (r = 0.906, p<0.0001), respectively. In conclusion, the proposed ratSUV and ratSUV glc provide a proxy for the K i and MR glc based on a single static [ 18 F]FDG PET SUV measurement improving clinical significance and translation of rodent studies. Given a defined strain, sex, age, diet, and weight range, this method is applicable for future experiments by converting SUV with the derived f(BW)., Competing Interests: Declaration of Competing Interest The authors declare no competing interest., (Copyright © 2021. Published by Elsevier Inc.)

Depending on the molar activity of the tracer, the maximal allowable injected activity in mouse brain PET studies can be extremely low in order to avoid receptor saturation. Therefore, a high level of noise can be present in the image. We investigate several dynamic PET reconstruction methods in reduced counts, or equivalently in reduced injected activity, data exemplified in [ 11 C]raclopride BP ND andR1quantification using the simplified reference tissue model (SRTM). We compared independent frame reconstruction (IFR), post-reconstruction HYPR denoising (IFR + HYPR), direct reconstruction using the SRTM model (DIR-SRTM), and the spatial (KERS) and spatiotemporal kernel reconstruction (KERST). Additionally, HYPR denoising of the frames used as features for the calculation of the spatial kernel matrix, was investigated (KERS-HYPR and KERST-HYPR). In vivo data of 11 mice, was used to generate list-mode data for five reduced count levels corresponding to reductions by a factor 4, 8, 12, 16 and 32 (equivalently 2.07, 1.04, 0.691, 0.518, and 0.260 MBq). Correlation of regional BP ND andR1values (reduced versus full counts reconstructions) was high (r > 0.94) for all methods, with KERS-HYPR and KERST-HYPR reaching the highest correlation ( r  > 0.96). Among methods with regularization, DIR-SRTM showed the largest variability in BP ND (Bland-Altman SD from 3.0% to 12%), while IFR showed it forR1(5.1%-14.6%). KERST and KERST-HYPR were the only methods with Bland-Altman bias and SD below 5% for noise level up to a reduction factor of 16. At the voxel level, BP ND andR1correlation was gradually decreased with increasing noise, with the largest correlation ( BP ND r  > 0.88,R1 r  > 0.62) for KERS-HYPR and KERST-HYPR. The spatial and the spatiotemporal kernel methods performed similarly, while using only temporal regularization with direct reconstruction showed more variability. Although R 1 values present noise, using the spatiotemporal kernel reconstruction, accurate estimates of binding potential could be obtained with mouse injected activities as low as 0.26-0.518 MBq. This is desirable in order to maintain the tracer kinetics principle in mouse studies., (Creative Commons Attribution license.)

Purpose: Our aim in this study was to compare different non-invasive pharmacokinetic models and assess test-retest reproducibility of the radioligand [ 11 C]SCH23390 for the quantification of dopamine D 1 -like receptor (D 1 R) in both wild-type (WT) mice and heterozygous (HET) Q175DN mice as Huntington's disease (HD) model., Procedures: Adult WT (n = 9) and HET (n = 14) mice underwent a 90-min [ 11 C]SCH23390 positron emission tomography (PET) scan followed by computed tomography (CT) to evaluate the pharmacokinetic modelling in healthy and diseased conditions. Additionally, 5 WT mice and 7 HET animals received a second [ 11 C]SCH23390 PET scan for test-retest reproducibility. Parallel assessment of the simplified reference tissue model (SRTM), the multilinear reference tissue model (MRTM) and the Logan reference tissue model (Logan Ref) using the striatum as a receptor-rich region and the cerebellum as a receptor-free (reference) region was performed to define the most suitable method for regional- and voxel-based quantification of the binding potential (BP ND ). Finally, standardised uptake value ratio (SUVR-1) was assessed as a potential simplified measurement., Results: For all models, we measured a significant decline in dopamine D 1 R density (e.g. SRTM = - 38.5 ± 5.0 %, p < 0.0001) in HET mice compared to WT littermates. Shortening the 90-min scan duration resulted in large underestimation of striatal BP ND in both WT mice (SRTM 60 min: - 17.7 ± 2.8 %, p = 0.0078) and diseased HET (SRTM 60 min: - 13.1 ± 4.1 %, p = 0.0001). Striatal BP ND measurements were very reproducible with an average test-retest variability below 5 % when using both MRTM and SRTM. Parametric BP ND maps generated with SRTM were highly reliable, showing nearly perfect agreement to the regional analysis (r 2  = 0.99, p < 0.0001). Finally, SRTM provided the most accurate estimate for relative tracer delivery R 1 with both regional- and voxel-based analyses. SUVR-1 at different time intervals were not sufficiently reliable when compared to BP ND (r 2  < 0.66)., Conclusions: Ninety-minute acquisition and the use of SRTM for pharmacokinetic modelling is recommended. [ 11 C]SCH23390 PET imaging demonstrates optimal characteristics for the study of dopamine D 1 R density in models of psychiatric and neurological disorders as exemplified in the Q175DN mouse model of HD.

We aimed to evaluate [3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-0- 11 C-methyloxime] ([ 11 C]ABP688) small animal positron emission tomography (μPET) as a biomarker to visualize possible longitudinal changes in metabotropic glutamate receptor 5 (mGluR5) availability in the brain of SAP90/PSD-95 associated protein 3 (Sapap3) knockout (ko) mice, showing obsessive compulsive disorder (OCD)-like behavior., Methods: Alongside the assessment of grooming, we performed [ 11 C]ABP688 μPET/CT imaging in wildtype (wt; n=10) and ko (n=11) mice both at 3 and 9 months. Using the simplified reference tissue method (SRTM), the nondisplaceable binding potential (BP ND ) was calculated representing the in vivo availability of the metabotropic glutamate receptor 5 (mGluR5) in the brain with the cerebellum as a reference region. Longitudinal voxel-based statistical parametric mapping (SPM) was performed on BP ND images. Results were verified using [ 11 C]ABP688 ex vivo autoradiography, [ 3 H]ABP688 in vitro autoradiography, and mGluR5 immunohistochemistry., Results: Cross-sectional comparisons revealed significantly increased grooming parameters in ko animals, at both time points. A significant longitudinal increase in % grooming duration (+268.25%; p<0.05) reflected aggravation of this behavior in ko mice. [ 11 C]ABP688 μPET revealed significantly lower mGluR5 availability in the cortex, striatum, hippocampus, and amygdala of ko mice at both ages. A significant longitudinal BP ND decline was present for ko mice (p<0.01: cortex -17.14%, striatum -19.82%, amygdala -23.57%; p<0.05: hippocampus -15.53%), which was confirmed by SPM (p<0.01)., Conclusion: Sapap3 ko mice show a decline in mGluR5 availability in OCD relevant brain regions parallel to the worsening of OCD-like behavior. This demonstrates a potential role for [ 11 C]ABP688 PET as a biomarker to monitor disease progression in vivo., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recent advances in positron emission tomography (PET) have allowed to perform brain scans of freely moving animals by using rigid motion correction. One of the current challenges in these scans is that, due to the PET scanner spatially variant point spread function (SVPSF), motion corrected images have a motion dependent blurring since animals can move throughout the entire field of view (FOV). We developed a method to calculate the image-based resolution kernels of the motion dependent and spatially variant PSF (MD-SVPSF) to correct the loss of spatial resolution in motion corrected reconstructions. The resolution kernels are calculated for each voxel by sampling and averaging the SVPSF at all positions in the scanner FOV where the moving object was measured. In resolution phantom scans, the use of the MD-SVPSF resolution model improved the spatial resolution in motion corrected reconstructions and corrected the image deformation caused by the parallax effect consistently for all motion patterns, outperforming the use of a motion independent SVPSF or Gaussian kernels. Compared to motion correction in which the SVPSF is applied independently for every pose, our method performed similarly, but with more than two orders of magnitude faster computation time. Importantly, in scans of freely moving mice, brain regional quantification in motion-free and motion corrected images was better correlated when using the MD-SVPSF in comparison with motion independent SVPSF and a Gaussian kernel. The method developed here allows to obtain consistent spatial resolution and quantification in motion corrected images, independently of the motion pattern of the subject.

Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [ 11 C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [ 11 C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [ 11 C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. V T (IDIF) values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p  < 0.0001), with 1TCM performing better than 2TCM for K 1 (IDIF) . A scan duration of 60 min was sufficient for reliable V C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [ T (IDIF) C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.K 1 (IDIF) estimations. In vivo metabolism of [ 11 C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [ 11 C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.

In small animal positron emission tomography (PET) studies, given the spatial resolution of preclinical PET scanners, quantification in small regions can be challenging. Moreover, in scans where animals are placed away from the center of the field of view (CFOV), e.g. in simultaneous scans of multiple animals, quantification accuracy can be compromised due to the loss of spatial resolution towards the edge of the FOV. Here, we implemented a spatially variant resolution model to improve quantification in small regions and to allow simultaneous scanning of multiple animals without compromising quantification accuracy. The scanner's point spread function (PSF) was characterized across the FOV and modelled using a spatially variant and asymmetric Gaussian function. The spatially variant PSF (SVPSF) was then used for resolution modelling in the iterative reconstruction. To assess the image quality, a line source phantom in a cold and warm background, as well as mouse brain [ 18 F]FDG scans, were performed. The SVPSF and the vendor's maximum a posteriori (MAP3D) reconstructions produced uniform spatial resolution across the scanner FOV, but MAP3D resulted in lower spatial resolution. The line sources recovery coefficient using SVPSF was similar at the CFOV and at the edge of the FOV. In contrast, the other tested reconstructions produced lower recovery coefficient at the edge of the FOV. In mouse brain reconstructions, less spill-over from hot regions to cold regions, as well as more symmetric regional brain uptake was observed using SVPSF. The contrast in brain images was the highest using SVPSF, in mice scanned at the CFOV and off-center. Incorporation of a spatially variant resolution model for small animal brain PET improves quantification accuracy in small regions and produces consistent image spatial resolution across the FOV. Therefore, simultaneous scanning of multiple animals can benefit by using spatially variant resolution modelling.

Impairment of group I metabotropic glutamate receptors (mGluRs) results in altered glutamate signalling, which is associated with several neurological disorders including Huntington's Disease (HD), an autosomal neurodegenerative disease. In this study, we assessed in vivo pathological changes in mGluR1 availability in the Q175DN mouse model of HD using longitudinal positron emission tomography (PET) imaging with the radioligand [ 11 C]ITDM. Ninety-minute dynamic PET imaging scans were performed in 22 heterozygous (HET) Q175DN mice and 22 wild-type (WT) littermates longitudinally at 6, 12, and 16 months of age. Analyses of regional volume of distribution with an image-derived input function (V T (IDIF) ) and voxel-wise parametric V T (IDIF) maps were performed to assess differences between genotypes. Post-mortem evaluation at 16 months was done to support in vivo findings. [ 11 C]ITDM V T (IDIF) quantification revealed higher mGluR1 availability in the brain of HET mice compared to WT littermates (e.g. cerebellum: + 15.0%, + 17.9%, and + 17.6% at 6, 12, and 16 months, respectively; p < 0.001). In addition, an age-related decline in [ 11 C]ITDM binding independent of genotype was observed between 6 and 12 months. Voxel-wise analysis of parametric maps and post-mortem quantifications confirmed the elevated mGluR1 availability in HET mice compared to WT littermates. In conclusion, in vivo measurement of mGluR1 availability using longitudinal [ 11 C]ITDM PET imaging demonstrated higher [ 11 C]ITDM binding in extra-striatal brain regions during the course of disease in the Q175DN mouse model.

Introduction: Dual-biomarker positron emission tomography (PET), providing complementary information on cerebral blood flow and amyloid-β deposition, is of clinical interest for Alzheimer's disease (AD). The purpose of this study was to validate the perfusion components of early-phase 18 F-florbetapir (eAV45), the 18 F-AV45 delivery rate (R1), and 18 F-FDG against 15 O-H 2 O PET and assess how they change with disease severity., Methods: This study included ten controls, 19 amnestic mild cognitive impairment, and 10 AD dementia subjects. Within-subject regional correlations between modalities, between-group regional and voxel-wise analyses of covariance per modality, and receiver operating characteristic analyses for discrimination between groups were performed., Results: FDG standardized uptake value ratio, eAV45 (0-2 min) standardized uptake value ratio, and AV45-R1 were significantly associated with H 2 O PET (regional Pearson r = 0.54-0.82, 0.70-0.94, and 0.65-0.92, respectively; P < .001). All modalities confirmed reduced cerebral blood flow in the posterior cingulate of patients with amnestic mild cognitive impairment and AD dementia, which was associated with lower cognition (r = 0.36-0.65, P < .025) and could discriminate between patient and control groups (area under the curve > 0.80). However, eAV45 was less sensitive to reflect the disease severity than AV45-R1 or FDG., Discussion: R1 is preferable over eAV45 for accurate representation of brain perfusion in dual-biomarker PET for AD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

PET scans of the mouse brain are usually performed with anesthesia to immobilize the animal. However, it is desirable to avoid the confounding factor of anesthesia in mouse-brain response. Methods: We developed and validated brain PET imaging of awake, freely moving mice. Head-motion tracking was performed using radioactive point-source markers, and we used the tracking information for PET-image motion correction. Regional 18 F-FDG brain uptake in a test, retest, and memantine-challenge study was measured in awake ( n = 8) and anesthetized ( n = 8) C57BL/6 mice. An awake uptake period was considered for the anesthesia scans. Results: Awake (motion-corrected) PET images showed an 18 F-FDG uptake pattern comparable to the pattern of anesthetized mice. The test-retest variability (represented by the intraclass correlation coefficient) of the regional SUV quantification in the awake animals (0.424-0.555) was marginally lower than that in the anesthetized animals (intraclass correlation coefficient, 0.491-0.629) over the different regions. The increased memantine-induced 18 F-FDG uptake was more pronounced in awake (+63.6%) than in anesthetized (+24.2%) animals. Additional behavioral information, acquired for awake animals, showed increased motor activity on a memantine challenge (total distance traveled, 18.2 ± 5.28 m) compared with test-retest (6.49 ± 2.21 m). Conclusion: The present method enables brain PET imaging on awake mice, thereby avoiding the confounding effects of anesthesia on the PET reading. It allows the simultaneous measurement of behavioral information during PET acquisitions. The method does not require any additional hardware, and it can be deployed in typical high-throughput scan protocols., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Awake rat brain positron emission tomography (PET) has previously been developed to avoid the influence of anesthesia on the rat brain response. In the present work, we further the awake rat brain scanning methodology to establish simultaneous scanning of two interacting rats in a high resolution, large field of view PET scanner. Awake rat imaging methodology based on point source tracking was adapted to be used in a dedicated human brain scanner, the ECAT high resolution research tomograph (HRRT). Rats could freely run on a horizontal platform of 19.4 × 23 cm placed inside the HRRT. The developed methodology was validated using a motion resolution phantom experiment, 3 awake single rat [ 18 F]FDG scans as well as an [ 18 F]FDG scan of 2 interacting rats. The precision of the point source based motion tracking was 0.359 mm (standard deviation). Minor loss of spatial resolution was observed in the motion corrected reconstructions (MC) of the resolution phantom compared to the motion-free reconstructions (MF). The full-width-at-half-maximum of the phantom rods were increased by on average 0.37 mm in the MC compared to the MF. During the awake scans, extensive motion was observed with rats moving throughout the platform area. The average rat head motion speed was 1.69 cm/s. Brain regions such as hippocampus, cortex and cerebellum could be recovered in the motion corrected reconstructions. Relative regional brain uptake of MC and MF was strongly correlated (Pearson's r ranging from 0.82 to 0.95, p < 0.0001). Awake rat brain PET imaging of interacting rats was successfully implemented on the HRRT scanner. The present method allows a large range of motion throughout a large field of view as well as to image two rats simultaneously opening the way to novel rat brain PET study designs., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Motion tracking with finite time sampling causing an associated unknown residual motion between two motion measurements is one of the factors contributing to resolution loss in small animal PET motion correction. The aim of this work is (i) to provide a means to estimate the effect of the finite motion sampling on the spatial resolution of the motion correction reconstructions and (ii) to correct for this residual motion thereby minimizing resolution loss. We calculate a tailored spatially variant deconvolution kernel from the measured motion data which is then used to deconvolve the motion corrected image using a 3D Richardson-Lucy algorithm. A simulation experiment of numerical phantoms as well as a microDerenzo phantom experiment wherein the phantom was manually moved at different speeds was performed to assess the performance of our proposed method. In the motion corrected images of the microDerenzo phantom there was an average rod FWHM differences between the slow and fast motion cases of 9.7%. This difference was reduced to 5.8% after applying the residual motion deconvolution. In awake animal experiments, the proposed method can serve to mitigate the finite sampling factor degrading the spatial resolution as well as the resolution differences between fast-moving and slow-moving animals. Graphical abstract Motion correction of positron emission tomography (PET) scans of moving subjects can be performed by measuring the motion of the subject during the PET scan with an optical tracking camera. The motion tracking data obtained from the tracking camera is then used to correct the PET image reconstructions for motion. Due to finite time sampling of the motion data, the motion corrected reconstructions suffer from loss of spatial resolution. In the proposed method, a spatially variant deconvolution kernel is calculated from the motion tracking data, which is then used to correct the motion-corrected PET reconstructions for the blurring effect of the finite motion sampling through a Richardson-Lucy deconvolution.

Background: amyloid-PET reading has been classically implemented as a binary assessment, although the clinical experience has shown that the number of borderline cases is non negligible not only in epidemiological studies of asymptomatic subjects but also in naturalistic groups of symptomatic patients attending memory clinics. In this work we develop a model to compare and integrate visual reading with two independent semi-quantification methods in order to obtain a tracer-independent multi-parametric evaluation., Methods: We retrospectively enrolled three cohorts of cognitively impaired patients submitted to 18 F-florbetaben (53 subjects), 18 F-flutemetamol (62 subjects), 18 F-florbetapir (60 subjects) PET/CT respectively, in 6 European centres belonging to the EADC. The 175 scans were visually classified as positive/negative following approved criteria and further classified with a 5-step grading as negative, mild negative, borderline, mild positive, positive by 5 independent readers, blind to clinical data. Scan quality was also visually assessed and recorded. Semi-quantification was based on two quantifiers: the standardized uptake value (SUVr) and the ELBA method. We used a sigmoid model to relate the grading with the quantifiers. We measured the readers accord and inconsistencies in the visual assessment as well as the relationship between discrepancies on the grading and semi-quantifications., Conclusion: It is possible to construct a map between different tracers and different quantification methods without resorting to ad-hoc acquired cases. We used a 5-level visual scale which, together with a mathematical model, delivered cut-offs and transition regions on tracers that are (largely) independent from the population. All fluorinated tracers appeared to have the same contrast and discrimination ability with respect to the negative-to-positive grading. We validated the integration of both visual reading and different quantifiers in a more robust framework thus bridging the gap between a binary and a user-independent continuous scale., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Activated microglia express the translocator protein (TSPO) on the outer mitochondrial membrane. 18 F-PBR111 is a second-generation PET ligand that specifically binds the TSPO, allowing in vivo visualization and quantification of neuroinflammation. The aim of this study was to evaluate whether the test-retest variability of 18 F-PBR111 in healthy controls is acceptable to detect a psychosis-associated neuroinflammatory signal in schizophrenia. Methods: Dynamic 90-min 18 F-PBR111 scans were obtained in 17 healthy male controls (HCs) and 11 male schizophrenia patients (SPs) during a psychotic episode. Prior genotyping for the rs6917 polymorphism distinguished high-affinity binders (HABs) and mixed-affinity binders (MABs). Total volume of distribution (V T ) was determined from 2-tissue-compartment modeling with vascular trapping and a metabolite-corrected plasma input function. A subgroup of HCs ( n = 12; 4 HABs and 8 MABs) was scanned twice to assess absolute test-retest variability and intraclass correlation coefficients of the regional V T values. Differences in TSPO binding between HC and SP were assessed using mixed model analysis adjusting for age, genotype, and age*cohort. The effect of using different scan durations (V T-60 min versus V T-90 min ) was determined based on Pearson r. Data were mean ± SD. Results: Mean absolute variability in V T ranged from 16% ± 14% (19% ± 20% HAB; 15% ± 11% MAB) in the cortical gray matter to 22% ± 15% (23% ± 15% HAB; 22% ± 16% MAB) in the hippocampus. Intraclass correlation coefficients were consistently between 0.64 and 0.82 for all tested regions. TSPO binding in SP compared with HC depended on age (cohort*age: P < 0.05) and was increased by +14% ± 4% over the regions. There was a significant effect of genotype on TSPO binding, and V T of HABs was 31% ± 8% (HC: 17% ± 5%, SP: 61% ± 14%) higher than MABs. Across all clinical groups, V T-60 min and V T-90 min were strongly correlated ( r > 0.7, P < 0.0001). Conclusion: 18 F-PBR111 can be used for monitoring of TSPO binding, as shown by medium test-retest variability and reliability of V T in HCs. Microglial activation is present in SPs depending on age and needs to be adjusted for genotype., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Quantification in positron emission tomography (PET) imaging of an orthotopic mouse model of colorectal cancer (CRC) is challenging due to difficult tumor delineation. We aimed to establish a reproducible delineation approach, evaluate its feasibility for reliable PET quantification and compare its added translational value with its subcutaneous counterpart., Procedures: A subcutaneous Colo205-luc2 tumor fragment harvested from a donor mouse was transplanted onto the caecum of nude mice, with (n = 10) or without (n = 10) the addition of an X-ray detectable thread. Animals underwent 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) PET imaging, complemented with X-ray computed tomography (CT) and magnetic resonance imaging (MRI, 7T). Animals without a thread underwent additional contrast enhanced (Exitron) CT imaging. Tumors were delineated on the MRI, μPET image or contrast enhanced μCT images and correlations between in vivo and ex vivo [ 18 F]FDG tumor uptake as well as between image-derived and caliper-measured tumor volume were evaluated. Finally, cancer hallmarks were assessed immunohistochemically for the characterization of both models., Results: Our results showed the strongest correlation between both in vivo and ex vivo uptake (r = 0.84, p < 0.0001) and image-derived and caliper-measured tumor volume (r = 0.96, p < 0.0001) when the tumor was delineated on the MR image. Orthotopic tumors displayed an abundance of stroma, higher levels of proliferation (p = 0.0007), apoptosis (p = 0.02), and necrosis (p < 0.0001), a higher number of blood vessels (p < 0.0001); yet lower tumor hypoxia (p < 0.0001) as compared with subcutaneous tumors., Conclusions: This orthotopic mouse model proved to be a promising tool for the investigation of CRC through preclinical imaging studies provided the availability of anatomical MR images for accurate tumor delineation. Furthermore, the tumor microenvironment of the orthotopic tumor resembled more that of human CRC, increasing its likelihood to advance translational nuclear imaging studies of CRC.

Increased brain uptake of 18 F-AV45 visualized by PET is a key biomarker for Alzheimer disease (AD). The SUV ratio (SUVR) is widely used for quantification, but is subject to variability based on choice of reference region and changes in cerebral blood flow. Here we validate the SUVR method against the gold standard volume of distribution (V T ) to assess cross-sectional differences in plaque load. Methods: Dynamic 60-min 18 F-AV45 (291 ± 67 MBq) and 1-min 15 O-H 2 O (370 MBq) scans were obtained in 35 age-matched elderly subjects, including 10 probable AD, 15 amnestic mild cognitive impairment (aMCI), and 10 cognitively healthy controls (HCs). 18 F-AV45 V T was determined from 2-tissue-compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50-60 min after injection, using either cerebellar gray matter (SUVR CB ) or whole subcortical white matter (SUVR WM ) as the reference. Additionally, whole cerebellum, pons, centrum semiovale, and a composite region were examined as alternative references. Blood flow was quantified by 15 O-H 2 O SUV. Data are presented as mean ± SEM. Results: There was rapid metabolization of 18 F-AV45, with only 35% of unchanged parent remaining at 10 min. Compared with V T , differences in cortical Aβ load between aMCI and AD were overestimated by SUVR WM (+4% ± 2%) and underestimated by SUVR CB (-10% ± 2%). V T correlated better with SUVR WM (Pearson r: from 0.63 for posterior cingulate to 0.89 for precuneus, P < 0.0001) than with SUVR CB (Pearson r: from 0.51 for temporal lobe [ P = 0.002] to 0.82 for precuneus [ P < 0.0001]) in all tested regions. Correlation results for the alternative references were in between those for CB and WM. 15 O-H 2 O data showed that blood flow was decreased in AD compared with aMCI in cortical regions (-5% ± 1%) and in the reference regions (CB, -9% ± 8%; WM, -8% ± 8%). Conclusion: Increased brain uptake of 18 F-AV45 assessed by the simplified static SUVR protocol does not truly reflect Aβ load. However, SUVR WM is better correlated with V T and more closely reflects V T differences between aMCI and AD than SUVR CB ., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Preclinical positron emission tomography (PET) imaging in small animals is generally performed under anesthesia to immobilize the animal during scanning. More recently, for rat brain PET studies, methods to perform scans of unrestrained awake rats are being developed in order to avoid the unwanted effects of anesthesia on the brain response. Here, we investigate the use of a projected structure stereo camera to track the motion of the rat head during the PET scan. The motion information is then used to correct the PET data. The stereo camera calculates a 3D point cloud representation of the scene and the tracking is performed by point cloud matching using the iterative closest point algorithm. The main advantage of the proposed motion tracking is that no intervention, e.g. for marker attachment, is needed. A manually moved microDerenzo phantom experiment and 3 awake rat [ 18 F]FDG experiments were performed to evaluate the proposed tracking method. The tracking accuracy was 0.33 mm rms. After motion correction image reconstruction, the microDerenzo phantom was recovered albeit with some loss of resolution. The reconstructed FWHM of the 2.5 and 3 mm rods increased with 0.94 and 0.51 mm respectively in comparison with the motion-free case. In the rat experiments, the average tracking success rate was 64.7%. The correlation of relative brain regional [ 18 F]FDG uptake between the anesthesia and awake scan reconstructions was increased from on average 0.291 (not significant) before correction to 0.909 (p  <  0.0001) after motion correction. Markerless motion tracking using structured light can be successfully used for tracking of the rat head for motion correction in awake rat PET scans.

Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1-42/Aβ1-40 ratio is used as compared to CSF Aβ1-42 levels alone., Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting., Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1-42, Aβ1-40, T-tau, P-tau181)., Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1-42/Aβ1-40 was applied compared to Aβ1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1-42/Aβ1-40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

Purpose: We evaluated the glucose metabolism after microinjections of a GABAA antagonist, bicuculline, and a GABAA agonist, muscimol, in the rat prelimbic cortex (PL) by small animal positron emission tomography (μPET)., Procedures: Following a microinjection of either 0.5 μl bicuculline (0.1 mg/ml), muscimol (1 mg/ml), or saline in the left PL of 11 healthy male Sprague Dawley rats (250-275 g), 2-deoxy-2-[(18)F]fluoro-β-D-glucose ([(18)F]FDG) PET images were acquired. Volume-of-interest (VOI)-based analysis and voxel-based statistical parametric mapping were performed (n = 9)., Results: VOI-based analysis revealed significantly different [(18)F]FDG uptake following bicuculline versus muscimol in PL (p < 0.001), infralimbic cortex (p < 0.01), and cingulate cortex (p < 0.01). Voxel-based analysis showed bicuculline induced widespread significant hypermetabolism throughout the brain while muscimol induced significant localized hypometabolism., Conclusions: Here, we visualize functional GABAA-mediated correlations of the PL following pharmacological stimulation. This could serve as a reference and shed light on the working and focality of other stimulation paradigms targeting this region.

Positron emission tomography studies of cerebral glucose utilization and amyloid-β deposition with fluoro-deoxy-D-glucose ([(18)F]-FDG) and amyloid tracers have shown characteristic pathological changes in Alzheimer's Disease that can be used for disease diagnosis and monitoring. Application of this technology to preclinical research with transgenic animal models would greatly facilitate drug discovery and further understanding of disease processes. The results from preclinical studies with these imaging biomarkers have however been highly inconsistent, causing doubts over whether animal models can truly replicate an AD-like phenotype. In this study we performed in vivo imaging with [(18)F]-FDG and [(18)F]-AV45 in double transgenic TASTPM mice, a transgenic model that been previously demonstrated high levels of fibrillar amyloid-β and decreases in cerebral glucose utilization with ex vivo techniques. Our results show widespread and significant retention of [(18)F]-AV45 (p < 0.0001) in aged TASTPM mice in addition to significant regional decreases in [(18)F]-FDG uptake (p < 0.05). In vivo quantification of amyloid-β showed a strong (Pearson's r = 0.7078), but not significant (p = 0.1156), positive correlation with ex vivo measures suggesting some limitations on tracer sensitivity. In the case of [(18)F]-FDG, voxelwise analysis greatly enhanced detection of hypometabolic regions. We further evidenced modest neuronal loss (thalamus p = 0.0318) that could underlie the observed hypometabolism. This research was performed in conjunction with the European Community's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under the PharmaCog Grant Agreement no.115009.

Purpose: Prefrontal cortex (PFC) deep brain stimulation (DBS) has been proposed as a therapy for addiction and depression. This study investigates changes in rat cerebral glucose metabolism induced by different DBS frequencies using μPET., Procedures: One hour DBS of the prelimbic area (PL) of the medial PFC (mPFC) (60 Hz, 130 Hz or sham) in rats (n = 9) was followed by 2-deoxy-2-[(18) F] fluoro-D-glucose ([(18) F]FDG) μPET., Results: Sixty Hz DBS elicited significant hypermetabolism in the ipsilateral PL ([(18) F]FDG uptake +5.2 ± 2.3 %, p < 0.05). At 130 Hz, hypometabolism was induced in the ipsilateral PL (-2.5 ± 2.6 %, non-significant). Statistical parametric mapping revealed hypo and hypermetabolism clusters for both 60 and 130 Hz versus sham and show a certain state of alertness (increased activity in sensory and motor-related regions) mainly for 60 Hz., Conclusions: This study suggests the potential of 60 Hz PL mPFC DBS for the treatment of disorders associated with prefrontal hypofunction.

An overview of the theory of 4D image reconstruction for emission tomography is given along with a review of the current state of the art, covering both positron emission tomography and single photon emission computed tomography (SPECT). By viewing 4D image reconstruction as a matter of either linear or non-linear parameter estimation for a set of spatiotemporal functions chosen to approximately represent the radiotracer distribution, the areas of so-called 'fully 4D' image reconstruction and 'direct kinetic parameter estimation' are unified within a common framework. Many choices of linear and non-linear parameterization of these functions are considered (including the important case where the parameters have direct biological meaning), along with a review of the algorithms which are able to estimate these often non-linear parameters from emission tomography data. The other crucial components to image reconstruction (the objective function, the system model and the raw data format) are also covered, but in less detail due to the relatively straightforward extension from their corresponding components in conventional 3D image reconstruction. The key unifying concept is that maximum likelihood or maximum a posteriori (MAP) estimation of either linear or non-linear model parameters can be achieved in image space after carrying out a conventional expectation maximization (EM) update of the dynamic image series, using a Kullback-Leibler distance metric (comparing the modeled image values with the EM image values), to optimize the desired parameters. For MAP, an image-space penalty for regularization purposes is required. The benefits of 4D and direct reconstruction reported in the literature are reviewed, and furthermore demonstrated with simple simulation examples. It is clear that the future of reconstructing dynamic or functional emission tomography images, which often exhibit high levels of spatially correlated noise, should ideally exploit these 4D approaches.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulation technique for the treatment of various neurological and psychiatric disorders. To investigate the working mechanism of this treatment approach, we designed a small-animal coil for dedicated use in rats and we combined this neurostimulation method with small-animal positron emission tomography (microPET or μPET) to quantify regional 2-deoxy-2-((18)F)fluoro-d-glucose ([(18)F]-FDG) uptake in the rat brain, elicited by a low- (1 Hz) and a high- (50 Hz) frequency paradigm. Rats (n=6) were injected with 1 mCi of [(18)F]-FDG 10 min after the start of 30 min of stimulation (1 Hz, 50 Hz or sham), followed by a 20-min μPET image acquisition. Voxel-based statistical parametric mapping (SPM) image analysis of 1-Hz and 50-Hz versus sham stimulation was performed. For both the 1-Hz and 50-Hz paradigms we found a large [(18)F]-FDG hypermetabolic cluster (2.208 mm(3) and 2.616 mm(3), resp.) (analysis of variance (ANOVA), p<0.05) located in the dentate gyrus complemented with an additional [(18)F]-FDG hypermetabolic cluster (ANOVA, p<0.05) located in the entorhinal cortex (2.216 mm(3)) for the 50-Hz stimulation. The effect on [(18)F]-FDG metabolism was 2.9 ± 0.8% at 1 Hz and 2.5 ± 0.8% at 50 Hz for the dentate gyrus clusters and 3.3 ± 0.5% for the additional cluster in the entorhinal cortex at 50 Hz. The maximal (4.19 vs. 2.58) and averaged (2.87 vs. 2.21) T-values are higher for 50 Hz versus 1 Hz. This experimental study demonstrates the feasibility to combine μPET imaging in rats stimulated with rTMS using a custom-made small-animal magnetic stimulation setup to quantify changes in the cerebral [(18)F]-FDG uptake as a measure for neuronal activity., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

The standard uptake value (SUV), commonly used to quantify (18)F-FluoroDeoxyGlucose (FDG) uptake in small animal brain PET imaging, is affected by many factors. In this study the influence of fasting times, inter-scan duration and repetitive scanning on the variability of different SUV measures is investigated. Additionally it is demonstrated that these variables could adversely influence the outcome of a pharmacological challenge when not accounted for. Naive Sprague-Dawley rats (n=20) were randomly divided into five different fasting groups (no fasting up to 24h of fasting). SUV brain uptake values were reproducible in naive animals when a fasting period of at least 12h is used and for shorter fasting periods SUV values need to be corrected for the glucose level. Additionally, a separate animal group (n=6) was sufficiently fasted for 16h and in a longitudinal setting being scanned six times in three weeks. Especially with short inter-scan durations, increasing glucose levels were found over time which was attributed to increased stress due to repeated food deprivation, altered food intake or scan manipulations. As a result, even with controlled and sufficient fasting, blood glucose levels should be taken into account for data quantification. Strikingly, even the brain activation effects of an NMDA-antagonist challenge with memantine could not be detected in experiments with a short inter-scan duration if glucose levels were not taken into account. Correcting for glucose levels decreases the inter- and intra-animal variability for rat brain imaging. SUV corrected for glucose levels yields the lowest inter-animal variation. However, if the body weight changes significantly, as in a long experiment, quantification based on the glucose corrected percentage injected dose (and not SUV) is recommendable as this yields the lowest intra-animal variation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The perception of aversive stimuli is essential for human survival and depends largely on environmental context. Although aversive brain processing has been shown to involve the sensorimotor cortex, the neural and biochemical mechanisms underlying the interaction between two independent aversive cues are unclear. Based on previous work indicating ventromedial prefrontal cortex (vmPFC) involvement in the mediation of context-dependent emotional effects, we hypothesized a central role for the vmPFC in modulating sensorimotor cortex activity using a GABAergic mechanism during an aversive-aversive stimulus interaction. This approach revealed differential activations within the aversion-related network (eg, sensorimotor cortex, midcingulate, and insula) for the aversive-aversive, when compared with the aversive-neutral, interaction. Individual differences in sensorimotor cortex signal changes during the aversive-aversive interaction were predicted by GABAA receptors in both vmPFC and sensorimotor cortex. Together, these results demonstrate the central role of GABA in mediating context-dependent effects in aversion-related processing.

Purpose: Positron emission tomography (PET) water activation studies can be considerably accelerated when the time between the successive water bolus injections is reduced. However, when considering shorter interinjection times, as short as 5 min, there will be a contaminating residual PET signal in brain tissues attributed to the previous injections. In this paper a signal separation methodology is proposed to allow shorter (<10 min) interinjection times., Methods: The contaminating signal in the frames of interest is estimated by extrapolating the decaying tail of the previous signal. The method requires the dynamic PET recording of the decaying signals between two injections in order to extrapolate the tail, which can be done post-reconstruction using a weighted least squares method. Several extrapolation functions are investigated, including a quadratic function, a decaying exponential, and a biologically inspired function. The biologically inspired function is based on the one-tissue compartmental model for [(15)O]H2O and makes use of a generating function estimated from the total trues coincidence rate. To evaluate the proposed method and extrapolation functions, one- and two-dimensional simulation studies were performed, using interinjection times as low as 5 min. The resulting corrected images are compared to the conventionally obtained images with an interinjection time of 10 min, which allows the previous signal to almost completely vanish., Results: Among all considered extrapolation functions the biologically inspired function was found to give the best results. The bias introduced when considering shorter interinjection times (<10 min) could be almost completely removed by subtracting the extrapolated remaining activity from the total measured signal of interest. Compared to the standard method of using longer interinjection times the resulting images have a slightly increased variance. Nonetheless the observed increases are small compared to the total variance and the resulting activation maps were visually very similar., Conclusions: The simulation results show that the proposed method can significantly reduce the total scan time (e.g., when considering 12 bolus injections, the total scan time can be reduced from 2 to 1 h). Extensive and very realistic simulations were used in this work, paving the way for future in vivo validation of the method.

A novel imaging and signal separation strategy is proposed to be able to separate [(18)F]FDG and multiple [(15)O]H(2)O signals from a simultaneously acquired dynamic PET acquisition of the two tracers. The technique is based on the fact that the dynamics of the two tracers are very distinct. By adopting an appropriate bolus injection strategy and by defining tailored sets of basis functions that model either the FDG or water component, it is possible to separate the FDG and water signal. The basis functions are inspired from the spectral analysis description of dynamic PET studies and are defined as the convolution of estimated generating functions (GFs) with a set of decaying exponential functions. The GFs are estimated from the overall measured head curve, while the decaying exponential functions are pre-determined. In this work, the time activity curves (TACs) are modelled post-reconstruction but the model can be incorporated in a global 4D reconstruction strategy. Extensive PET simulation studies are performed considering single [(18)F]FDG and 6 [(15)O]H(2)O bolus injections for a total acquisition time of 75 min. The proposed method is evaluated at multiple noise levels and different parameters were estimated such as [(18)F]FDG uptake and blood flow estimated from the [(15)O]H(2)O component, requiring a full dynamic analysis of the two components, static images of [(18)F]FDG and the water components as well as [(15)O]H(2)O activation. It is shown that the resulting images and parametric values in ROIs are comparable to images obtained from separate imaging, illustrating the feasibility of simultaneous imaging of [(18)F]FDG and [(15)O]H(2)O components.

This work explores the feasibility and impact of including both the motion correction and the image registration transformation parameters from positron emission tomography (PET) image space to magnetic resonance (MR), or stereotaxic, image space within the system matrix of PET image reconstruction. This approach is motivated by the fields of neuroscience and psychiatry, where PET is used to investigate differences in activation patterns between different groups of participants, requiring all images to be registered to a common spatial atlas. Currently, image registration is performed after image reconstruction which introduces interpolation effects into the final image. Furthermore, motion correction (also requiring registration) introduces a further level of interpolation, and the overall result of these operations can lead to resolution degradation and possibly artifacts. It is important to note that performing such operations on a post-reconstruction basis means, strictly speaking, that the final images are not ones which maximize the desired objective function (e.g. maximum likelihood (ML), or maximum a posteriori reconstruction (MAP)). To correctly seek parameter estimates in the desired spatial atlas which are in accordance with the chosen reconstruction objective function, it is necessary to include the transformation parameters for both motion correction and registration within the system modeling stage of image reconstruction. Such an approach not only respects the statistically chosen objective function (e.g. ML or MAP), but furthermore should serve to reduce the interpolation effects. To evaluate the proposed method, this work investigates registration (including motion correction) using 2D and 3D simulations based on the high resolution research tomograph (HRRT) PET scanner geometry, with and without resolution modeling, using the ML expectation maximization (MLEM) reconstruction algorithm. The quality of reconstruction was assessed using bias-variance and root mean squared error analyses, comparing the proposed method to conventional post-reconstruction registration methods. An overall reduction in bias (for a cold region: from 41% down to 31% (2D) and 97% down to 65% (3D), and for a hot region: from 11% down to 8% (2D) and from 16% down to 14% (3D)) and in root mean squared error analyses (for a cold region: from 43% to 37% (2D) and from 97% to 65% (3D), and for a hot region: from 11% to 9% (2D) and from 16% down to 14% (3D)) in reconstructed regional mean activities (full regions of interest; all with statistical significance: p < 5 × 10(-10)) is found when including the motion correction and registration in the system matrix of the MLEM reconstruction, with resolution modeling. However, this improvement in performance comes with an extra computational cost of about 40 min. In this context, this work constitutes an important step toward the goal of estimating parameters of interest directly from the raw Poisson-distributed PET data, and hence toward the complete elimination of post-processing steps.

Task-based selection of image reconstruction methodology in emission tomography is a critically important step when designing a PET study. This paper concerns optimizing, given the measured data of the study only, reconstruction performance for a range of quantification tasks: finding the mean radioactivity concentration for different regions of interests (ROIs), different ROI sizes and different group sizes (i.e. the number of subjects in the PET study). At present, the variability of quantification performance of different reconstruction methods, according to both the ROI and group sizes, is largely ignored. In this paper, it is shown that both the ROI and group size have a tremendous impact on the error of the estimator for the task of ROI quantification. A study-specific, task-oriented and space-variant selection rule is proposed that selects a close to optimal estimate drawn from a series of estimates obtained by filtered backprojection (FBP) and different OSEM (ordered subset expectation maximization) iterations. The optimality criterion is to minimize an estimated mean square error (MSE), where the MSE is estimated from the data in the study using the bootstrap resampling technique. The proposed approach is appropriate for both pixel-level estimates and ROI estimates in single- and multi-subject studies. An extensive multi-trial simulation study using a 2D numerical phantom and relevant count levels shows that the proposed selection rule can produce quantitative estimates that are close to the estimates that minimize the true MSE (where the true MSE can only be obtained from many independent Monte-Carlo realizations with knowledge of the ground truth). This indicates that with the proposed selection rule one can obtain a close to optimal estimate while avoiding the critical step of selecting user-defined reconstruction settings (such as an OSEM iteration number or the choice between FBP and OSEM). In this initial 2D study, only FBP and OSEM reconstruction methods are considered but the proposed selection rule should readily generalize to different estimators (i.e. different reconstruction algorithms) and 3D imaging.

Purpose: Motion during PET data acquisition is either introduced by design (e.g., couch wobble to enrich data sampling) or through unintentional motion of the object under study (e.g., subject head motion). Prior to this present work, such effects have been considered within distinctly different frameworks in PET imaging, with a rather basic approach having been devised for the cases of intentional motion (such as couch wobble or bed translation) in contrast to the relatively advanced modeling approaches devised for object motion. This article unifies the treatment of these different types of acquisition motion within a generalized framework through the use of the PET supersets data format. From this general framework, a range of conventional motion-compensation methods can be examined as special cases, permitting a revealing investigation into both the suboptimality of commonly adopted approximations, as well as the beneficial impact of known acquisition motion on image quality., Methods: The PET superset data format is a data representation ideally suited for the (potentially lossless) combination of conventional PET data with complementary motion information. Different practical implementations for the reconstruction from PET superset data involving varying levels of approximation to facilitate computation are identified and their impact on the final reconstructed image quality is assessed. Three main simulated case studies are investigated: (i) Motion compensation for subject head motion for 18F-FDG imaging, (ii) motion exploitation using either couch wobble or random motion, and (iii) motion exploitation using involuntary object motion both with and without couch wobble occurring. The motion exploitation case study goes beyond merely correcting for motion: The motion is directly modeled by the iterative reconstruction to exploit the increased sampling which is available to the benefit of reconstructed image quality., Results: Reconstruction from superset data was successfully demonstrated for the case of motion correction for a 18F-FDG brain phantom simulation. Building on this success, the methodology was then applied to the case of motion exploitation. The case study resulted in three important findings. First, only reconstruction implementations which model the motion directly within the iterative reconstruction can succeed in significantly improving image resolution and contrast recovery for a given reconstructed noise level. Therefore, the commonly adopted approximation of binning the motion-adjusted data (which is the only method reported to date in the literature) is suboptimal and underestimates the beneficial impact of methods such as wobble during acquisition. Second, similar improvements were found for both types of motion patterns: Periodic wobble motion as well as random motion. Finally, for the case of simulated realistic involuntary object motion, similar resolution improvements were found (both with and without couch wobble)., Conclusions: The proposed superset framework allows comprehensive analysis of the commonly adopted approximations when considering motion in PET reconstruction. The findings demonstrate that the supersets data format successfully unify reconstruction in the presence of different sources of known acquisition motion into one framework, and as a result leads to hitherto unreported image quality improvements for all the cases tested where the object motion is accurately known.

Purpose: Studies have shown that Monte Carlo-based reconstruction could effectively improve the image quality of positron emission tomography. The authors have previously used a Gaussian rotator-based algorithm to efficiently reduce the computational cost for system matrix (SM) calculation and to meet the large memory requirements for SM storage. However, pronounced ringing artifacts were observed in the reconstructed image. In this article, the authors investigated and characterized these artifacts., Methods: The authors proposed an "ideal" rotator and used it as a baseline in the artifacts evaluation. This ideal rotator produces perfectly rotated images. The Gaussian rotator method was evaluated by a full system model and a partial system model without positron range and acolinearity, which could be compensated for by the blurring of the Gaussian rotator for 18F studies. Noiseless data, Monte Carlo simulation data, as well as acquired experimental data were used to quantitatively characterize the behavior of the artifacts., Results: The study of the noiseless data indicated that the artifacts were mainly attributed to the rotator, which further blurred the simulated system responses. The simulation study suggested that the artifacts become less pronounced and not quantitatively significant in practice. This result is consistent with the experimental data study. Better contrast recovery was achieved with an over-compensated system model. Traditionally, an undercompensated system model was preferred to avoid artifacts. The authors' studies suggest that the Gaussian rotator with the full system model yields the best image quality among the evaluated methods with considerably reduced quantitative error and quantitatively insignificant artifacts in practice., Conclusions: The authors' investigation indicated that a moderately overcompensated system model (about 2 mm FWHM in this study) yielded better contrast recovery and quantitatively insignificant artifacts in practice.

Fully 4D PET image reconstruction is receiving increasing research interest due to its ability to significantly reduce spatiotemporal noise in dynamic PET imaging. However, thus far in the literature, the important issue of correcting for subject head motion has not been considered. Specifically, as a direct consequence of using temporally extensive basis functions, a single instance of movement propagates to impair the reconstruction of multiple time frames, even if no further movement occurs in those frames. Existing 3D motion compensation strategies have not yet been adapted to 4D reconstruction, and as such the benefits of 4D algorithms have not yet been reaped in a clinical setting where head movement undoubtedly occurs. This work addresses this need, developing a motion compensation method suitable for fully 4D reconstruction methods which exploits an optical tracking system to measure the head motion along with PET superset data to store the motion compensated data. List-mode events are histogrammed as PET superset data according to the measured motion, and a specially devised normalization scheme for motion compensated reconstruction from the superset data is required. This work proceeds to propose the corresponding time-dependent normalization modifications which are required for a major class of fully 4D image reconstruction algorithms (those which use linear combinations of temporal basis functions). Using realistically simulated as well as real high-resolution PET data from the HRRT, we demonstrate both the detrimental impact of subject head motion in fully 4D PET reconstruction and the efficacy of our proposed modifications to 4D algorithms. Benefits are shown both for the individual PET image frames as well as for parametric images of tracer uptake and volume of distribution for (18)F-FDG obtained from Patlak analysis.

Purpose: Several studies have shown the benefit of an accurate system modeling using Monte Carlo techniques. For state-of-the-art whole-body positron emission tomography (PET) scanners, Monte Carlo-based image reconstruction is associated with a significant computational cost to calculate the system matrix as well as a large memory capacity to store it. In this article, the authors present a simulation-reconstruction framework to solve these problems on the Philips Gemini GS PET scanner., Methods: A fast, realistic system matrix simulation module was developed using egs&#95;pet, which is an efficient PET simulation code based on EGSnrc. The generated system matrix was then used in a rotator-based ordered subset expectation maximization (OS-EM) algorithm, which exploits the rotational symmetry of a cylindrical PET scanner. The system matrix was further compressed by using sparse storage techniques., Results: The system matrix simulation took five days on 50 cores of Xeon 2.66 GHz, resulting in a system matrix of 2.01 GB. The entire system matrix could be stored in the main memory of a standard personal computer. The image quality in terms of contrast-noise trade-offs was considerably improved compared to a standard OS-EM algorithm. The image quality was also compared to the clinical software on the scanner using routine parameter settings. The contrast recovery coefficient of small hot spheres and cold spheres was significantly improved., Conclusions: The results indicated that the proposed framework could be used for this PET scanner with improved image quality. This method could also be applied to other state-of-the-art whole-body PET scanners and preclinical PET scanners with a similar shape.

Purpose: The aim of this study is to optimize different parameters in the time-of-flight (TOF) reconstruction for the Philips GEMINI TF. The use of TOF in iterative reconstruction introduces additional variables to be optimized compared to conventional PET reconstruction. The different parameters studied are the TOF kernel width, the kernel truncation (used to reduce reconstruction time) and the scatter correction method., Methods: These parameters are optimized using measured phantom studies. All phantom studies were acquired with a very high number of counts to limit the effects of noise. A high number of iterations (33 subsets and 3 iterations) was used to reach convergence. The figures of merit are the uniformity in the background, the cold spot recovery and the hot spot contrast. As reference results we used the non-TOF reconstruction of the same data sets., Results: It is shown that contrast recovery loss can only be avoided if the kernel is extended to more than 3 standard deviations. To obtain uniform reconstructions the recommended scatter correction is TOF single scatter simulation (SSS). This also leads to improved cold spot recovery and hot spot contrast. While the daily measurements of the system show a timing resolution in the range of 590–600 ps, the optimal reconstructions are obtained with a TOF kernel full-width at half-maximum (FWHM) of 650–700 ps. The optimal kernel width seems to be less critical for the recovered contrast but has an important effect on the background uniformity. Using smaller or wider kernels results in a less uniform background and reduced hot and cold contrast recovery., Conclusion: The different parameters studied have a large effect on the quantitative accuracy of the reconstructed images. The optimal settings from this study can be used as a guideline to make an objective comparison of the gains obtained with TOF PET versus PET reconstruction.

The GEANT4 application for tomographic emission (GATE) is one of the most detailed Monte Carlo simulation tools for SPECT and PET. It allows for realistic phantoms, complex decay schemes, and a large variety of detector geometries. However, only a fraction of the information in each particle history is available for postprocessing. In order to extend the analysis capabilities of GATE, a flexible framework was developed. This framework allows all detected events to be subdivided according to their type: In PET, true coincidences from others, and in SPECT, geometrically collimated photons from others. The framework of the authors can be applied to any isotope, phantom, and detector geometry available in GATE. It is designed to enhance the usability of GATE for the study of contamination and for the investigation of the properties of current and future prototype detectors. The authors apply the framework to a case study of Bexxar, first assuming labeling with 124I, then with 131I. It is shown that with 124I PET, results with an optimized window improve upon those with the standard window but achieve less than half of the ideal improvement. Nevertheless, 124I PET shows improved resolution compared to 131I SPECT with triple-energy-window scatter correction.

Tomographic reconstruction from positron emission tomography (PET) data is an ill-posed problem that requires regularization. An attractive approach is to impose an l(1) -regularization constraint, which favors sparse solutions in the wavelet domain. This can be achieved quite efficiently thanks to the iterative algorithm developed by Daubechies et al., 2004. In this paper, we apply this technique and extend it for the reconstruction of dynamic (spatio-temporal) PET data. Moreover, instead of using classical wavelets in the temporal dimension, we introduce exponential-spline wavelets (E-spline wavelets) that are specially tailored to model time activity curves (TACs) in PET. We show that the exponential-spline wavelets naturally arise from the compartmental description of the dynamics of the tracer distribution. We address the issue of the selection of the "optimal" E-spline parameters (poles and zeros) and we investigate their effect on reconstruction quality. We demonstrate the usefulness of spatio-temporal regularization and the superior performance of E-spline wavelets over conventional Battle-LemariE wavelets in a series of experiments: the 1-D fitting of TACs, and the tomographic reconstruction of both simulated and clinical data. We find that the E-spline wavelets outperform the conventional wavelets in terms of the reconstructed signal-to-noise ratio (SNR) and the sparsity of the wavelet coefficients. Based on our simulations, we conclude that replacing the conventional wavelets with E-spline wavelets leads to equal reconstruction quality for a 40% reduction of detected coincidences, meaning an improved image quality for the same number of counts or equivalently a reduced exposure to the patient for the same image quality.

The use of a temporal B-spline basis for the reconstruction of dynamic positron emission tomography data was investigated. Maximum likelihood (ML) reconstructions using an expectation maximization framework and maximum A-posteriori (MAP) reconstructions using the generalized expectation maximization framework were evaluated. Different parameters of the B-spline basis of such as order, number of basis functions and knot placing were investigated in a reconstruction task using simulated dynamic list-mode data. We found that a higher order basis reduced both the bias and variance. Using a higher number of basis functions in the modeling of the time activity curves (TACs) allowed the algorithm to model faster changes of the TACs, however, the TACs became noisier. We have compared ML, Gaussian postsmoothed ML and MAP reconstructions. The noise level in the ML reconstructions was controlled by varying the number of basis functions. The MAP algorithm penalized the integrated squared curvature of the reconstructed TAC. The postsmoothed ML was always outperformed in terms of bias and variance properties by the MAP and ML reconstructions. A simple adaptive knot placing strategy was also developed and evaluated. It is based on an arc length redistribution scheme during the reconstruction. The free knot reconstruction allowed a more accurate reconstruction while reducing the noise level especially for fast changing TACs such as blood input functions. Limiting the number of temporal basis functions combined with the adaptive knot placing strategy is in this case advantageous for regularization purposes when compared to the other regularization techniques.

Tomographic reconstruction from PET data is an ill-posed problem that requires regularization. Recently, Daubechies et al. [1] proposed an l (1) regularization of the wavelet coefficients that can be optimized using iterative thresholding schemes. In this paper, we extend this approach for the reconstruction of dynamic (spatio-temporal) PET data. Instead of using classical wavelets in the temporal dimension, we introduce exponential-spline wavelets that are specially tailored to model time activity curves (TACs) in PET. We show the usefulness of spatio-temporal regularization and the superior performance of E-spline wavelets over conventional Battle-Lemarié wavelets for a 1-D TAC fitting experiment and a tomographic reconstruction experiment.