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Objectives: We sought to investigate whether positron emission tomography/computed tomography (CT) angiography using [11C]-PK11195, a selective ligand for peripheral benzodiazepine receptors expressed in activated macrophages, can be used to image vascular inflammation. Background: Activated macrophages and T lymphocytes are fundamental elements in the pathogenesis of large-vessel vasculitides. Methods: Fifteen patients (age 52+/-16 years) with systemic inflammatory disorders (6 consecutive symptomatic patients with clinical suspicion of active vasculitis and 9 asymptomatic control patients) underwent positron emission tomography with [11C]-PK11195 and CT angiography. [11C]-PK11195 uptake was measured by calculating target-to-background ratios of activity normalized to venous blood. Results: Coregistration of positron emission tomography with contrast-enhanced CT angiography facilitated localization of [11C]-PK11195 arterial wall uptake. Visual analysis revealed focal [11C]-PK11195 uptake in the arterial wall of all 6 symptomatic patients, but in none of the asymptomatic controls. Although serum inflammatory biomarkers (C-reactive protein, erythrocyte sedimentation rate, white cell count) did not differ significantly between the 2 groups, symptomatic patients had increased [11C]-PK11195 vascular uptake (target-to-background ratio 2.41+/-1.59 vs. 0.98+/-0.10; p=0.001). Conclusions: By binding to activated macrophages in the vessel wall, [11C]-PK11195 enables noninvasive imaging of vascular inflammation. Alternative longer-lived radioligands for probing peripheral benzodiazepine receptors are being tested for wider clinical applications. [ABSTRACT FROM AUTHOR]

The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y 1 , Y 2 , Y 4 , and Y 5 . A growing body of evidence suggest the involvement of the NPY system in several cancers, notably the Y 5 subtype, thus acting as a relevant target for the development of radiopharmaceuticals for imaging or targeted radionuclide therapy (TRT). Here, the [cPP(1-7),NPY(19-23),Ala 31 ,Aib 32 ,Gln 34 ]hPP scaffold, further referred to as sY 5 ago, was modified with a DOTA chelator and radiolabeled with 68 Ga and 111 In and investigated in vitro and in vivo using the MCF-7 model. For in vivo studies, MCF-7 cells were orthotopically implanted in female nude mice and imaging with small animal positron emission tomography/computed tomography (μPET/CT) was performed. At the end of imaging, the mice were sacrificed. A scrambled version of sY 5 ago, which was also modified with a DOTA chelator, served as a negative control (DOTA-[Nle]sY 5 ago&#95;scrambled). sY 5 ago and DOTA-sY 5 ago showed subnanomolar affinity toward the Y 5 (0.9 ± 0.1 and 0.8 ± 0.1 nM, respectively) and a single binding site at the Y 5 was identified. [ 68 Ga]Ga-DOTA-sY 5 ago and [ 111 In]In-DOTA-sY 5 ago were hydrophilic and showed high specific internalization (1.61 ± 0.75%/10 6 cells at 1 h) and moderate efflux (55% of total binding externalized at 45 min). On μPET/CT images, most of the signal was depicted in the kidneys and the liver. MCF-7 tumors were clearly visualized. On biodistribution studies, [ 68 Ga]Ga-DOTA-sY 5 ago was eliminated by the kidneys (∼60 %ID/g). The kidney uptake is Y 5 -mediated. A specific uptake was also noted in the liver (5.09 ± 1.15 %ID/g vs 1.13 ± 0.21 %ID/g for [ 68 Ga]Ga-DOTA-[Nle]sY 5 ago&#95;scrambled, p < 0.05), the lungs (1.03 ± 0.34 %ID/g vs 0.20 %ID/g, p < 0.05), and the spleen (0.85 ± 0.09%ID/g vs 0.16 ± 0.16%ID/g, p < 0.05). In MCF-7 tumors, [ 68 Ga]Ga-DOTA-sY 5 ago showed 12-fold higher uptake than [ 68 Ga]Ga-DOTA-[Nle]sY 5 ago&#95;scrambled (3.43 ± 2.32 vs 0.27 ± 0.15 %ID/g, respectively, p = 0.0008) at 1 h post-injection. Finally, a proof-of-principle tissular micro-imaging study on a human primary cancer sample showed weak binding of [ 111 In]In-DOTA-sY 5 ago in prostatic intra-neoplasia and high binding in the ISUP1 lesion while normal prostate was free of signal.

Introduction: Alzheimer's disease is associated with sleep disturbances and accumulation of cerebral amyloid beta. The objective was to examine whether actigraphy-detected sleep parameters might be biomarkers for early amyloid burden., Methods: Participants underwent a week of actigraphy and an amyloid positron emission tomography (PET) scan. Sleep duration and continuity disruption (sleep fragmentation and nocturnal awakenings) were extracted and compared between amyloid-positive and amyloid-negative participants. Then multiple linear regressions were used between mean or night-to-night intra-individual variability (standard deviation) of sleep parameters and brain amyloid burden in a voxel-wise analysis., Results: Eighty-six subjects were included (80.3 ± 5.4 years; 48.8% of women). Amyloid-positive participants had a higher variability of sleep fragmentation compared to amyloid-negative participants. This parameter was associated with a higher amyloid burden in the frontal and parietal regions, and in the precuneus, in the whole sample., Discussion: This study highlights the relevance of using variability in sleep continuity as a potential biomarker of early amyloid pathogenesis., Competing Interests: All authors declare that they have no conflicts of interest., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Neurotensin receptor 2 (NTS 2 ) is a well-known mediator of central opioid-independent analgesia. Seminal studies have highlighted NTS 2 overexpression in a variety of tumors including prostate cancer, pancreas adenocarcinoma, and breast cancer. Herein, we describe the first radiometalated neurotensin analogue targeting NTS 2 . JMV 7488 (DOTA-(βAla) 2 -Lys-Lys-Pro-(D)Trp-Ile-TMSAla-OH) was prepared using solid-phase peptide synthesis, then purified, radiolabeled with 68 Ga and 111 In, and investigated in vitro on HT-29 cells and MCF-7 cells, respectively, and in vivo on HT-29 xenografts. [ 68 Ga]Ga-JMV 7488 and [ 111 In]In-JMV 7488 were quite hydrophilic (logD 7.4 = -3.1 ± 0.2 and -2.7 ± 0.2, respectively, p < 0.0001). Saturation binding studies showed good affinity toward NTS 2 ( K D = 38 ± 17 nM for [ 68 Ga]Ga-JMV 7488 on HT-29 and 36 ± 10 nM on MCF-7 cells; K D = 36 ± 4 nM for [ 111 In]In-JMV 7488 on HT-29 and 46 ± 1 nM on MCF-7 cells) and good selectivity (no NTS 1 binding up to 500 nM). On cell-based evaluation, [ 68 Ga]Ga-JMV 7488 and [ 111 In]In-JMV 7488 showed high and fast NTS 2 -mediated internalization of 24 ± 5 and 25 ± 11% at 1 h for [ 111 In]In-JMV 7488, respectively, along with low NTS 2 -membrane binding (<8%). Efflux was as high as 66 ± 9% at 45 min for [ 68 Ga]Ga-JMV 7488 on HT-29 and increased for [ 111 In]In-JMV 7488 up to 73 ± 16% on HT-29 and 78 ± 9% on MCF-7 cells at 2 h. Maximum intracellular calcium mobilization of JMV 7488 was 91 ± 11% to that of levocabastine, a known NTS 2 agonist on HT-29 cells demonstrating the agonist behavior of JMV 7488. In nude mice bearing HT-29 xenograft, [ 68 Ga]Ga-JMV 7488 showed a moderate but promising significant tumor uptake in biodistribution studies that competes well with other nonmetalated radiotracers targeting NTS 2 . Significant uptake was also depicted in lungs. Interestingly, mice prostate also demonstrated [ 68 Ga]Ga-JMV 7488 uptake although the mechanism was not NTS 2 -mediated., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Stomach cancer is the fifth most common cancer in terms of prevalence and incidence and the fourth leading cause of mortality in men and women worldwide. It is well-established that aberrant DNA methylation in cells can lead to carcinogenesis. The primary objective of our study was to investigate the aberrant DNA methylation status of genes associated with stomach cancer with a particular reference to the ethnic population of Mizoram, North East India. The site-level analysis identified 2883 CpG sites differentially methylated, representing ∼922 genes. Out of which 476 Differentially Methylated Positions (DMPs) were promoter-associated, 452 DMPs were hypermethylated, and 24 were hypomethylated. The region-level analysis identified 462 Differentially Methylated Regions (DMRs) corresponding to ∼320 genes, of which ∼281 genes were hypermethylated and ∼40 genes were hypomethylated. TCGA analysis showed that some of the genes had been previously implicated in other cancers including stomach cancer. Five hypermethylated genes were selected as candidate genes for further investigations and they have shown to be novel and could serve as candidate hypermethylation biomarkers for stomach cancer in this particular ethnic group., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: This study aimed to investigate the results of compartmental modeling (CM) and spectral analysis (SA) generated with dynamic 18F-FMISO tumor images. Besides, the regular tissue-to-blood ratio (TBR) images were derived and compared with the dynamic models., Methods: Nine subjects with glioblastoma underwent PET/CT imaging with the 18F-FMISO tracer. The protocol for PET imaging began with 15 min in dynamic mode and two 10-min duration static images at 120 min and 180 min post-injection. We used the two-tissue compartmental model for CM at the voxel basis, and we conducted SA to estimate the 18F-FMISO accumulation within each voxel. We also investigated the usual tumor-to-blood ratio (TBR) for comparison., Results: The images of the tumor showed different patterns of hypoxia and necrosis as a function of PET scanning times, while CM and SA methods based on dynamic PET imaging equally located tumor hypoxia. The mean correlation of K i  images of all subjects between CM and SA was 0.63 ± 0.19 (0.24-0.86). CM produced less noisy K i images than SA, and, in the contrary, SA produced accumulation component images more clear than with CM. CM- K i and SA-K i images were correlated with TBR images ( r = 0.72 ± 0.20 and 0.56 ± 0.26, respectively). In the only subject having a continuously increasing tumor time-activity curve, the k 3 image showed a high uptake in the necrosis region which was not apparent in TBR or K i images., Conclusion: Based on these results, the combination of CM and SA approaches was found more appropriate in generating voxel-based hypoxia images., Competing Interests: Conflict of InterestRedha-alla Abdo, Frédéric Lamare, Philippe Fernandez, and M’hamed Bentourkia declare no conflict of interest., (© Korean Society of Nuclear Medicine 2021.)

Early-onset torsion dystonia (TOR1A/DYT1) is a devastating hereditary motor disorder whose pathophysiology remains unclear. Studies in transgenic mice suggested abnormal cholinergic transmission in the putamen, but this has not yet been demonstrated in humans. The role of the cerebellum in the pathophysiology of the disease has also been highlighted but the involvement of the intrinsic cerebellar cholinergic system is unknown. In this study, cholinergic neurons were imaged using PET with 18F-fluoroethoxybenzovesamicol, a radioligand of the vesicular acetylcholine transporter (VAChT). Here, we found an age-related decrease in VAChT expression in the posterior putamen and caudate nucleus of DYT1 patients versus matched controls, with low expression in young but not in older patients. In the cerebellar vermis, VAChT expression was also significantly decreased in patients versus controls, but independently of age. Functional connectivity within the motor network studied in MRI and the interregional correlation of VAChT expression studied in PET were also altered in patients. These results show that the cholinergic system is disrupted in the brain of DYT1 patients and is modulated over time through plasticity or compensatory mechanisms., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Loss of medullary serotonin (5-hydroxytryptamine) neurons has been linked to respiratory disturbances in multiple system atrophy (MSA). Broader 5-hydroxytryptamine dysfunction may contribute to additional motor/nonmotor symptoms in MSA. The objective of this study was to compare brain 5-hydroxytryptamine 1A receptor binding between MSA and healthy controls. Secondary objectives were to compare 5-hydroxytryptamine 1A receptor binding between MSA and Parkinson's disease (PD) and to assess potential associations with motor/nonmotor symptoms in MSA., Methods: 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine positron emission tomography was performed in matched MSA patients (n = 16), PD patients (n = 15), and healthy controls (n = 18)., Results: 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios were lower in MSA patients versus healthy controls in several brain regions including the caudate, raphe nuclei, thalamus, and brain stem. Distribution volume ratios were also lower in brain stem and amygdala in MSA versus PD. Moderate associations were found between 2'-methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios and fatigue, pain, and apathy in MSA., Conclusion: Our results demonstrate 5-hydroxytryptamine dysfunction in several brain regions in MSA, which may contribute to fatigue, pain, and apathy. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Several independent studies have demonstrated the overexpression of NTS 1 in various malignancies, which make this receptor of interest for imaging and therapy. To date, radiolabeled neurotensin analogues suffer from low plasmatic stability and thus insufficient availability for high uptake in tumors. We report the development of 68 Ga-radiolabeled neurotensin analogues with improved radiopharmaceutical properties through the introduction of the silicon-containing amino acid trimethylsilylalanine (TMSAla). Among the series of novel radiolabeled neurotensin analogues, [ 68 Ga] Ga- JMV6659 exhibits high hydrophilicity (log D 7.4 = -3.41 ± 0.14), affinity in the low nanomolar range toward NTS 1 ( K d = 6.29 ± 1.37 nM), good selectivity ( K d NTS 1 / K d NTS 2 = 35.9), and high NTS 1 -mediated internalization. It has lower efflux and prolonged plasmatic half-life in human plasma as compared to the reference compound ([ 68 Ga]Ga-JMV6661 bearing the minimum active fragment of neurotensin and the same linker and chelate as other analogues). In nude mice bearing HT-29 xenograft, [ 68 Ga]Ga-JMV6659 uptake reached 7.8 ± 0.54 %ID/g 2 h post injection. Uptake was decreased to 1.38 ± 0.71 %ID/g with injection of excess of non-radioactive neurotensin. Radiation dose as extrapolated to human was estimated as 2.35 ± 0.6 mSv for a standard injected activity of 100MBq. [ 68 Ga]Ga-JMV6659 was identified as a promising lead compound suitable for PET imaging of NTS 1 -expressing tumors.

Gliomas are the most common type of primary brain tumors and are classified as grade IV. Necrosis and hypoxia are essential diagnostic features which result in poor prognosis of gliomas. The aim of this study was to report quantitative temporal analyses aiming at determining the hypoxic regions in glioblastoma multiforme and to suggest an optimal time for the clinical single scan of hypoxia. Nine subjects were imaged with PET and 18F-FMISO in dynamic mode for 15 min followed with static scans at 2, 3 and 4 h post-injection. Spectral analysis, tumor-to-blood ratio (TBR) and tumor-to-normal tissue ratio (TNR) were used to delimit perfused and hypoxic tumor regions. TBR and TNR images were further scaled by thresholding at 1.2, 1.4, 2 and 2.5 levels. The images showed a varying tumor volume with time. TBR produced broader images of the tumor than TNR considering the same thresholds on intensity. Spectral analysis reliably determined hypoxia with different degrees of perfusion. By comparing TBR and TNR with spectral analysis images, weak to moderate correlation coefficients were found for most thresholding values and imaging times (range: 0 to 0.69). Hypoxic volume (HV) estimated from the net uptake rate (K i ) were changing among imaging times. The minimum HV changes were found between 3 h and 4 h, confirming that after 3 h, there was a very low exchange of 81F-FMISO between blood and tumor. On the other hand, hypoxia started to dominate the perfused tissue at 90 min, suggesting this time is suitable for a single scan acquisition irrespective of tumor status being highly hypoxic or perfused. At this time, TBR and TNR were respectively found in the nine subjects as 1.72 ± 0.22 and 1.74 ± 0.19.

Objective: 3'-Deoxy-3'-[18F] fluorothymidine (18F-FLT) is a marker of cell proliferation and displays a high tumor-to-background ratio in brain tumor lesions. We determined whether combining 18F-FLT PET and MRI study improves the detection of tumoral tissue compared to MRI alone and whether 18F-FLT uptake has a prognostic value by studying its association with histopathological features., Methods: Thirteen patients with a supratentorial malignant glioma were recruited and scheduled for surgery. The tumor volume was defined in all patients on both 18F-FLT PET and MRI images. The images were coregistered and uploaded onto a neuronavigation system. During surgery, an average of 11 biopsies per patient were taken in regions of the brain that were positive to one or both imaging modalities, as well as from control peritumoral regions. The standardized uptake values (SUVs) of each biopsy region were correlated to histopathological data (i.e., proliferation index and number of mitoses) and the SUV values of high and low-grade samples were compared., Results: Out of a total of 149 biopsies, 109 contained tumoral tissue at histopathological analysis. The positive predictive value was 93.1% for MRI alone and 78.3% for MRI and PET combined. In addition, 40% of the biopsy samples taken from areas of the brain that were negative at both PET and MRI had evidence of malignancy at pathology. The SUV values were not significantly correlated to either the proliferation index or the number of mitoses, and could not differentiate between high- and low-grade samples., Conclusion: In patients with newly diagnosed glioma, a combination of MRI and 18F-FLT-PET detects additional tumoral tissue and this may lead to a more complete surgical resection. Also, the addition of a negative PET to a negative MRI increases the negative predictive value. However, 18F-FLT still underestimated the margins of the lesion and did not correlate with histopathological features.

Aim: The purpose of this study was to locate the levels of hypoxia in glioblastoma PET images measured with 18F-fluoromisonidazole in human subjects. It is recognized that tumors with hypoxia are resistant to treatment by radiotherapy and chemotherapy. Methods: The images were acquired in dynamic mode for 15 min or 30 min and in static mode for two single scans at 2 h and 3 h to allow the accumulation of the radiotracer in the tumor. The images were analyzed at the voxel basis with compartmental analysis (CA) and with the usual tumor-to-blood uptake ratio (TBR). Kmeans algorithm was applied to cluster the levels of hypoxia in the images. Results: TBR at a threshold of 1.2 at imaging times of 15 min, 2 h and 3 h produced images with different clusters. Also, the comparison of TBR with the distribution volume obtained with CA had a similarity index of 0.61 ± 0.05. Conclusion: We found some differences in defining the hypoxic volume within a tumor using TBR. The compartmental analysis allowed discrimination of the tumor hypoxic sub-volumes which can be useful for a better treatment with radiotherapy., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2019.)

In tomographic medical imaging (PET, SPECT, CT), differences in data acquisition and organization are a major hurdle for the development of tomographic reconstruction software. The implementation of a given reconstruction algorithm is usually limited to a specific set of conditions, depending on the modality, the purpose of the study, the input data, or on the characteristics of the reconstruction algorithm itself. It causes restricted or limited use of algorithms, differences in implementation, code duplication, impractical code development, and difficulties for comparing different methods. This work attempts to address these issues by proposing a unified and generic code framework for formatting, processing and reconstructing acquired multi-modal and multi-dimensional data. The proposed iterative framework processes in the same way elements from list-mode (i.e. events) and histogrammed (i.e. sinogram or other bins) data sets. Each element is processed separately, which opens the way for highly parallel execution. A unique iterative algorithm engine makes use of generic core components corresponding to the main parts of the reconstruction process. Features that are specific to different modalities and algorithms are embedded into specific components inheriting from the generic abstract components. Temporal dimensions are taken into account in the core architecture. The framework is implemented in an open-source C++ parallel platform, called CASToR (customizable and advanced software for tomographic reconstruction). Performance assessments show that the time loss due to genericity remains acceptable, being one order of magnitude slower compared to a manufacturer's software optimized for computational efficiency for a given system geometry. Specific optimizations were made possible by the underlying data set organization and processing and allowed for an average speed-up factor ranging from 1.54 to 3.07 when compared to more conventional implementations. Using parallel programming, an almost linear speed-up increase (factor of 0.85 times number of cores) was obtained in a realistic clinical PET setting. In conclusion, the proposed framework offers a substantial flexibility for the integration of new reconstruction algorithms while maintaining computation efficiency.

Respiratory motion reduces both the qualitative and quantitative accuracy of PET images in oncology. This impact is more significant for quantitative applications based on kinetic modeling, where dynamic acquisitions are associated with limited statistics due to the necessity of enhanced temporal resolution. The aim of this study is to address these drawbacks, by combining a respiratory motion correction approach with temporal regularization in a unique reconstruction algorithm for dynamic PET imaging. Elastic transformation parameters for the motion correction are estimated from the non-attenuation-corrected PET images. The derived displacement matrices are subsequently used in a list-mode based OSEM reconstruction algorithm integrating a temporal regularization between the 3D dynamic PET frames, based on temporal basis functions. These functions are simultaneously estimated at each iteration, along with their relative coefficients for each image voxel. Quantitative evaluation has been performed using dynamic FDG PET/CT acquisitions of lung cancer patients acquired on a GE DRX system. The performance of the proposed method is compared with that of a standard multi-frame OSEM reconstruction algorithm. The proposed method achieved substantial improvements in terms of noise reduction while accounting for loss of contrast due to respiratory motion. Results on simulated data showed that the proposed 4D algorithms led to bias reduction values up to 40% in both tumor and blood regions for similar standard deviation levels, in comparison with a standard 3D reconstruction. Patlak parameter estimations on reconstructed images with the proposed reconstruction methods resulted in 30% and 40% bias reduction in the tumor and lung region respectively for the Patlak slope, and a 30% bias reduction for the intercept in the tumor region (a similar Patlak intercept was achieved in the lung area). Incorporation of the respiratory motion correction using an elastic model along with a temporal regularization in the reconstruction process of the PET dynamic series led to substantial quantitative improvements and motion artifact reduction. Future work will include the integration of a linear FDG kinetic model, in order to directly reconstruct parametric images.

Cholinergic alterations in dementia with Lewy bodies (DLB) have been widely documented in postmortem studies, whereas in vivo studies are sparse, particularly at the subcortical level. We used 123 I-iodobenzovesamicol, a SPECT radiotracer of the vesicular acetylcholine transporter, to evaluate in vivo in DLB the integrity of the 3 main cholinergic pathways-the Ch1 (septohippocampal), the Ch4 (innominatocortical), and the Ch5 (pontothalamic) cholinergic pathways-as well as the striatal cholinergic interneurons. In addition, we assessed the involvement of the cholinergic system in cognitive and neuropsychiatric disorders in DLB patients., Methods: Twelve healthy volunteers (median age, 72 y; interquartile range, 6.25 y) and 11 DLB patients (median age, 76 y; interquartile range, 10.50 y) underwent a dynamic 123 I-iodobenzovesamicol SPECT scan and an MRI scan. MR images were automatically segmented, providing the volumes of several regions of interest, including the striatum and cholinergic terminals in Ch1 (hippocampus), Ch4 (cortical lobes), and Ch5 (thalamus). For each region of interest and each subject, pharmacokinetic modeling allowed calculation of the nondisplaceable binding potential (BP ND ) values for the binding of 123 I-iodobenzovesamicol to the vesicular acetylcholine transporter. A neuropsychological evaluation of participants was performed with the Mini-Mental State Examination and the Grober-Buschke, Set, visual discrimination, Benton, and Wechsler tests, and cognitive fluctuations and apathy were also assessed., Results: Compared with BP ND values for healthy subjects, BP ND values for DLB patients were significantly lower in the Ch4 terminal regions of the anterior cingulate cortex and the superior and inferior parietal cortices (P = 0.0006, 0.0015, and 0.0023, respectively), in the Ch5 terminal region of the thalamus (P = 0.0003), and in the striatum (P = 0.0042). All of the neuropsychological test scores were significantly lower in DLB patients than in healthy subjects. Four DLB patients with apathy and 4 DLB patients without apathy were identified. For the anterior cingulate cortex, compared with BP ND values in healthy subjects, BP ND values were significantly lower in patients with apathy (P = 0.004) and were unchanged in patients without apathy., Conclusion: Our results confirm the existence in DLB of cholinergic alterations, reaching both cortical and subcortical levels, including the Ch5 pathway and the striatum. Alterations in cholinergic transmission in the anterior cingulate cortex could be closely associated with the development of apathy., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Respiratory and cardiac motion causes qualitative and quantitative inaccuracies in whole body multi-modality imaging such as positron emission tomography coupled with computed tomography (PET/CT) and positron emission tomography/magnetic resonance imaging (PET/MRI). Solutions presented to date include motion synchronized PET and corresponding anatomical acquisitions (four dimensional [4D] PET/CT, 4D PET/MR), frequently referred to as the gating approach. This method is based on the acquisition of an external surrogate using an external device (pressure belt, optical monitoring system, spirometer etc.), subsequently used to bin PET and CT or MR anatomical data into a number of gates. A first limitation of this method is the low signal to noise ratio (SNR) of the resulting motion synchronized PET frames, given that every reconstructed frame contains only part of the count statistics available throughout a motion average PET acquisition. Another limitation is that the complex motion of internal organs cannot be fully estimated, characterized and modelled using a mono-dimensional motion signal. In order to resolve such issues, many advanced techniques have been proposed which include three consecutive major steps. These are based on firstly acquiring an external or internal motion surrogate, estimating or modelling the internal motion using anatomical information extracted from 4D anatomical images (CT and/or MR) and finally correcting for motion either in the PET raw data space, the image space or incorporate it within the PET image reconstruction which is the most optimal based motion correction method in PET/CT and in PET/MR imaging. Current research efforts are concentrating on combining the last two steps within a joint motion estimation/motion correction approach, the exploitation of MRI specific motion characterization sequences and the combination of both respiratory and cardiac motion corrections. The goal of this review is to present and discuss the different steps of all these motion correction methods in PET/CT and PET/MR imaging for whole body applications.

Unlabelled: The performance of an average SUV over a 1-mL-volume sphere within an (18)F-FDG-positive lesion resulting in the highest possible value (SUVpeakW) was compared with that of an average SUV computed from the 40 hottest voxels, irrespective of their location within the lesion (SUVmax-40)., Methods: Dynamic PET performed in 20 lung cancer lesions yielded for each SUV metric its mean value, relative measurement error, and repeatability (MEr-R)., Results: SUVpeakW mean value was significantly 9.66% lower than that of SUVmax-40 (P < 0.0001). SUVpeakW and SUVmax-40 MEr-R were significantly lower than the MEr-R of SUVmax (the hottest voxel): 9.35%-13.21% and 8.84%-12.49% versus 13.86%-19.59%, respectively, (95% confidence limit; P < 0.0001). Although being marginal, SUVpeakW MEr-R was not significantly greater than SUVmax-40 MEr-R (P = 0.086)., Conclusion: SUVmax-40 is more likely to represent the most metabolically active portions of tumors than SUVpeakW, with close variability performance., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: (123)I-iodobenzovesamicol is a SPECT radioligand selective for the vesicular acetylcholine transporter (VAChT) and used to assess the integrity of cholinergic pathways in various neurologic disorders. The current noninvasive method for quantitative analysis of (123)I-iodobenzovesamicol, based on multilinear reference tissue model 2 (MRTM2), requires repeated scans for several hours, limiting its application in clinical trials. Our objective was to validate a simplified acquisition method based on a single (123)I-iodobenzovesamicol static scan preserving the quantification accuracy. Three acquisition times were tested comparatively to a kinetic analysis using MRTM2., Methods: Six healthy volunteers underwent a dynamic SPECT acquisition comprising 14 frames over 28 h and an MR imaging scan. MR images were automatically segmented, providing the volumes of 19 regions of interest (ROIs). SPECT datasets were coregistered with MR images, and regional time-activity curves were derived. For each ROI, a complete MRTM2 pharmacokinetic analysis, using the cerebellar hemispheres as the reference region, led to the calculation of a (123)I-iodobenzovesamicol-to-VAChT binding parameter, the nondisplaceable binding potential (BP(ND-MRTM2)). A simplified analysis was also performed at 5, 8, and 28 h after injection, providing a simplified BP(ND), given as BP(ND-t) = C(ROI) - C(cerebellar hemispheres)/C(cerebellar hemispheres), with C being the averaged radioactive concentration., Results: No significant difference was found among BP(ND-5 h), BP(ND-8 h), and BP(ND-MRTM2) in any of the extrastriatal regions explored. BP(ND-28 h) was significantly higher than BP(ND-5 h), BP(ND-8 h), and BP(ND-MRTM2) in 9 of the 17 regions explored (P < 0.05). BP(ND-5 h), BP(ND-8 h), and BP(ND-28 h) correlated significantly with BP(ND-MRTM2) (P < 0.05; ρ = 0.99, 0.98, and 0.92, respectively). In the striatum, BP(ND-28 h) was significantly higher than BP(ND-5 h) and BP(ND-8 h). BP(ND-5 h) differed significantly from BP(ND-MRTM2) (P < 0.05), with BP(ND-5 h) being 43.6% lower., Conclusion: In the extrastriatal regions, a single acquisition at 5 or 8 h after injection provides quantitative results similar to a pharmacokinetic analysis. However, with the highest correlation and accuracy, 5 h is the most suitable time to perform an accurate (123)I-iodobenzovesamicol quantification. In the striatum, none of the 3 times has led to an accurate quantification., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: Partial volume effect (PVE) plays an important role in both qualitative and quantitative PET image accuracy, especially for small structures. A previously proposed voxelwise PVE correction method applied on PET reconstructed images involves the use of Lucy-Richardson deconvolution incorporating wavelet-based denoising to limit the associated propagation of noise. The aim of this study is to incorporate the deconvolution, coupled with the denoising step, directly inside the iterative reconstruction process to further improve PVE correction., Methods: The list-mode ordered subset expectation maximization (OSEM) algorithm has been modified accordingly with the application of the Lucy-Richardson deconvolution algorithm to the current estimation of the image, at each reconstruction iteration. Acquisitions of the NEMA NU2-2001 IQ phantom were performed on a GE DRX PET/CT system to study the impact of incorporating the deconvolution inside the reconstruction [with and without the point spread function (PSF) model] in comparison to its application postreconstruction and to standard iterative reconstruction incorporating the PSF model. The impact of the denoising step was also evaluated. Images were semiquantitatively assessed by studying the trade-off between the intensity recovery and the noise level in the background estimated as relative standard deviation. Qualitative assessments of the developed methods were additionally performed on clinical cases., Results: Incorporating the deconvolution without denoising within the reconstruction achieved superior intensity recovery in comparison to both standard OSEM reconstruction integrating a PSF model and application of the deconvolution algorithm in a postreconstruction process. The addition of the denoising step permitted to limit the SNR degradation while preserving the intensity recovery., Conclusions: This study demonstrates the feasibility of incorporating the Lucy-Richardson deconvolution associated with a wavelet-based denoising in the reconstruction process to better correct for PVE. Future work includes further evaluations of the proposed method on clinical datasets and the use of improved PSF models.

Quantitative imaging with PET requires accurate measurements of the amount of radioactivity injected into the patient and the concentration of radioactivity in a given region. Recently, new positron emitters, such as (124)I, (89)Zr, (82)Rb, (68)Ga, and (64)Cu, have emerged to promote PET development, but standards are still largely lacking. Therefore, we propose to validate a simple, robust, and replicable methodology, not requiring the use of any standards, to accurately calibrate a dose-calibrator for any β(+)-emitter. On the basis of (18)F cross-calibration, routinely performed with fluorine-18-fluorodeoxyglucose (F-FDG) in nuclear medicine departments, a methodology was developed using β(+)-emitting' phantoms to cross-calibrate the dose-calibrator for measuring the activity of positron emitters and quantifying the standardized uptake value (SUV). Ga phantoms filled with activities measured with various dose-calibrator settings were imaged to establish calibration curves (SUV values as a function of the dose-calibrator settings) and to identify the setting value, yielding an SUV value of 1.00 g/ml, reflecting an accurate measurement of (68)Ga activity. Activities measured with the identified setting were finally checked with a γ-counter. The setting of 772±1 was identified as ensuring that the studied dose-calibrator is correctly calibrated for (68)Ga to ensure an SUV value of 1.00±0.01 g/ml. γ-Ray spectrometry confirmed the accurate measurement of Ga activities by the dose-calibrator (relative error of 2.9±1.5%). We have developed a phantom-based method to accurately standardize dose-calibrators for any β(+)-emitter, without any standards.

Background: The aim of this study was to assess if FDG-PET could guide dose prescription heterogeneity and decrease arbitrary location of hotspots in SBRT., Methods: For three patients with stage I lung cancer, a CT-simulation and a FDG-PET were registered to define respectively the PTVCT and the biological target volume (BTV). Two plans involving volumetric modulated arc therapy (VMAT) and simultaneous integrated boost (SIB) were calculated. The first plan delivered 4 × 12 Gy within the PTV(CT) and the second plan, with SIB, 4 × 12 Gy and 13.8 Gy (115% of the prescribed dose) within the PTV(CT) and the BTV respectively. The Dmax-PTV(CT) had to be inferior to 60 Gy (125% of the prescribed dose). Plans were evaluated through the D95%, D99% and Dmax-PTV(CT), the D2 cm, the R50% and R100% and the dice similarity coefficient (DSC) between the isodose 115% and BTV. DSC allows verifying the location of the 115% isodose (ideal value = 1)., Results: The mean PTV(CT) and BTV were 36.7 (±12.5) and 6.5 (±2.2) cm3 respectively. Both plans led to similar target coverage, same doses to the OARs and equivalent fall-off of the dose outside the PTV(CT). On the other hand, the location of hotspots, evaluated through the DSC, was improved for the SIB plans with a mean DSC of 0.31 and 0.45 for the first and the second plans respectively., Conclusions: Use of PET to decrease arbitrary location of hotspots is feasible with VMAT and SIB for lung cancer.

Aim: PET/CT is widely used for the detection of lymph node involvement in head and neck squamous cell carcinoma (HNSCC). However, PET qualitative and quantitative capabilities are hindered by partial volume effects (PVE). Therefore, a retrospective study on 32 patients (57 lymph nodes) was carried out to evaluate the potential improvement of PVE correction (PVEC) in FDG PET/CT imaging for the diagnosis of HNSCC. Histopathological analysis of lymph nodes following neck dissection was used as the gold standard., Methods: A previously proposed deconvolution based PVEC approach was used to derive improved quantitative accuracy PET images, while the anatomical lymph node volumes were determined on the CT images. Different parameters including SUVmax and SUVmean were derived from both original and PVEC PET images for each patient., Results: Histopathology confirmed that SUVmax and SUVmean after PVEC allows a statistically significant differentiation of malignant and benign lymph nodes (P<0.05). The sensitivity of SUVmax and SUVmean was 64% and 57% respectively with or without PVEC. PVEC increased specificity from 71% to 76% for SUVmax and 57% to 66% for SUVmean. Corresponding accuracy increased from 66% to 71% for SUVmax and from 59% to 66% for SUVmean. However, the most accurate differentiation between benign and malignant nodes was obtained while using the magnitude of SUVmax increase after PVEC with a corresponding sensitivity, specificity and accuracy of 77%, 82% and 80% respectively., Conclusion: Our work shows that the use of partial volume effects correction allows a more accurate nodal staging using FDG PET imaging in HNSCC.

Aim: PET/CT is widely used for the detection of lymph node involvement in head and neck squamous cell carcinoma (HNSCC). However, PET qualitative and quantitative capabilities are hindered by partial volume effects (PVE). Therefore, a retrospective study on 32 patients (57 lymph nodes) was carried out to evaluate the potential improvement of PVE correction (PVEC) in FDG PET/CT imaging for the diagnosis of HNSCC. Histopathological analysis of lymph nodes following neck dissection was used as the gold standard. Methods: A previously proposed deconvolution based PVEC approach was used to derive improved quantitative accuracy PET images, while the anatomical lymph node volumes were determined on the CT images. Different parameters including SUVmax and SUVmean were derived from both original and PVEC PET images for each patient. Results: Histopathology confirmed that SUVmax and SUVmean after PVEC allows a statistically significant differentiation of malignant and benign lymph nodes (p<0.05). The sensitivity of SUVmax and SUVmean was 64% and 57% respectively with or without PVEC. PVEC increased specificity from 71% to 76% for SUVmax and 57% to 66% for SUVmean. Corresponding accuracy increased from 66% to 71% for SUVmax and from 59% to 66% for SUVmean. However, the most accurate differentiation between benign and malignant nodes was obtained while using the magnitude of SUVmax increase after PVEC with a corresponding sensitivity, specificity and accuracy of 77%, 82% and 80% respectively. Conclusion: Our work shows that the use of partial volume effects correction allows a more accurate nodal staging using FDG PET imaging in HNSCC.

Unlabelled: We evaluated in vivo the integrity of brain cholinergic pathways in Multiple System Atrophy (MSA) and the relationship between cholinergic dysfunction and motor disturbances, by measuring the vesicular acetylcholine transporter (VAChT) expression using Single Photon Emission Computed Tomography (SPECT) and [(123)I]-iodobenzovesamicol ([(123)I]-IBVM)., Methods: Nine patients with probable MSA and 12 healthy volunteers underwent a dynamic [(123)I]-IBVM SPECT-CT scan and a magnetic resonance imaging (MRI) scan. All patients were examined with the Unified MSA Rating Scale (UMSARS; subscale I = activities of daily living (ADL), II = motor and IV = disability). CT and MRI images were used to register the dynamic SPECT image to the Montreal Neurological Institute brain template, which includes the regions of interest (ROI) of striatum and Ch1 (medial septum nucleus-hippocampus), Ch4 (nucleus basalis of Meynert-cortex) and Ch5-Ch6 (pedunculopontine and laterodorsal tegmental nuclei-thalamus) cholinergic pathways. For each ROI, pharmacokinetic modeling of regional time activity curves led to the calculation of [(123)I]-IBVM to VAChT binding potential (BPND) value, proportional to VAChT expression., Results: When compared to controls, BPND values for MSA in Ch5-Ch6 were significantly decreased in both the pedunculopontine-laterodorsal nuclei and the thalamus (p = 0.004 and p = 0.006, respectively). Additionally, thalamus BPND values were correlated with UMSARS ADL (p = 0.006), motor (p = 0.002) and disability (p = 0.02) sub-scores. UMSARS motor subscale items 13 (postural instability) and 14 (gait) were also correlated with thalamus BPND values (p = 0.04)., Conclusion: Ch5-Ch6 are the most affected cholinergic pathways in MSA at both cell bodies and thalamic cholinergic terminals. These results underscore the relevant role of [(123)I]-IBVM SPECT for improving our understanding of the pathophysiology in MSA.

Brain anatomy variability is a major problem in quantifying functional images in nuclear medicine, in particular relative to aging and neurodegenerative diseases. The aim of this study was to compare affine and elastic model-based methods for magnetic resonance imaging (MRI) to brain atlas registration and to assess their impact on the quantification of cholinergic neurotransmission. Patients with multiple system atrophy (MSA) and age-matched healthy subjects underwent an MRI and a single-photon emission computed tomographic (SPECT) examination using [123I]-iodobenzovesamicol (IBVM). Both affine and elastic methods were compared to register the subjects' MRI with the Montreal Neurological Institute brain atlas. Performance of the registration accuracy was quantitatively assessed and the impact on the IBVM quantification was studied. For both subject groups, elastic registration achieved better quantitative performance compared to the affine model. For patients suffering from neurogenerative disease, this study demonstrates the importance and relevance of MRI to atlas registration in quantification of neuronal integrity. In this context, in comparison with rigid registrations, an elastic model-based registration provides the best relocation of the brain structures to the atlas for accurately quantifying cholinergic neurotransmission.

Unlabelled: Respiratory motion can potentially reduce accuracy in anatomic and functional image fusion from multimodality systems. It can blur the uptake of small lesions and lead to significant activity underestimation. Solutions presented to date include respiration-synchronized anatomic and functional acquisitions. To increase the signal-to-noise ratio of the synchronized PET images, methods using nonrigid transformations during the reconstruction process have been proposed. In most of these methods, 4-dimensional (4D) CT images were used to derive the required deformation matrices. However, variations between acquired 4D PET and corresponding CT image series due to differences in respiratory conditions during PET and CT acquisitions have been reported. In addition, the radiation dose burden resulting from a 4D CT acquisition may not be justifiable for every patient., Methods: In this paper, we present a method for the generation of dynamic CT images from the combination of one reference CT image and deformation matrices obtained from the elastic registration of 4D PET images not corrected for attenuation. On the one hand, our approach eliminates the need for the acquisition of dynamic CT. On the other hand, it also ensures a good match between CT and PET images, allowing accurate attenuation correction to be performed for respiration-synchronized PET acquisitions., Results: The proposed method was first validated on Monte Carlo-simulated datasets, and then on patient datasets (n = 4) by comparing generated 4D CT images with the corresponding acquired original CT images. Different levels of PET image statistical quality were considered in order to investigate the impact of image noise in the derivation of the 4D CT series., Conclusion: Our results suggest that clinically relevant PET acquisition times can be used for the implementation of such an approach, making this an even more attractive solution considering the absence of the extra dose given by a standard 4D CT acquisition. Finally, this approach may be applicable to other multimodality devices such as PET/MR.