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Purpose We present a cross-sectional study comparing hypometabolism and atrophy patterns in Niemann–Pick disease type C (NP-C). We also present a longitudinal analysis of NP-C [18F]FDG-PET data. Methods 22 patients NP-C patients underwent MRI and [18F]FDG-PET imaging at baseline, and a subset of 12 patients were able to complete at least one follow-up PET imaging acquisition. Visual assessment and group-level voxel- and region-based analyses of the baseline MRI and PET images were performed by comparing our NP-C cohort to PET and MRI healthy volunteer cohorts. Per cent changes in metabolism (%/year/region) were calculated for longitudinal analysis. Results Significant atrophy was present in the cerebellum (p 18F]FDG PET provided stronger effect sizes and was able to show significant hypometabolism even in areas without atrophy. [18F]FDG uptake annual changes (p 18F]FDG PET as a tool for the assessment of cross-sectional and longitudinal neurodegeneration in NP-C.

Purpose SimPET (www.sim-pet.org) is a free cloud-based platform for the generation of realistic brain positron emission tomography (PET) data. In this work, we introduce the key features of the platform. In addition, we validate the platform by performing a comparison between simulated healthy brain FDG-PET images and real healthy subject data for three commercial scanners (GE Advance NXi, GE Discovery ST, and Siemens Biograph mCT). Methods The platform provides a graphical user interface to a set of automatic scripts taking care of the code execution for the phantom generation, simulation (SimSET), and tomographic image reconstruction (STIR). We characterize the performance using activity and attenuation maps derived from PET/CT and MRI data of 25 healthy subjects acquired with a GE Discovery ST. We then use the created maps to generate synthetic data for the GE Discovery ST, the GE Advance NXi, and the Siemens Biograph mCT. The validation was carried out by evaluating Bland-Altman differences between real and simulated images for each scanner. In addition, SPM voxel-wise comparison was performed to highlight regional differences. Examples for amyloid PET and for the generation of ground-truth pathological patients are included. Results The platform can be efficiently used for generating realistic simulated FDG-PET images in a reasonable amount of time. The validation showed small differences between SimPET and acquired FDG-PET images, with errors below 10% for 98.09% (GE Discovery ST), 95.09% (GE Advance NXi), and 91.35% (Siemens Biograph mCT) of the voxels. Nevertheless, our SPM analysis showed significant regional differences between the simulated images and real healthy patients, and thus, the use of the platform for converting control subject databases between different scanners requires further investigation. Conclusions The presented platform can potentially allow scientists in clinical and research settings to perform MC simulation experiments without the need for high-end hardware or advanced computing knowledge and in a reasonable amount of time.

Background We aim to provide a systematic study of the impact of white matter (WM) spill-in on the calculation of standardized uptake value ratios (SUVRs) on Aβ-negative subjects, and we study the effect of including WM in the reference region as a compensation. In addition, different partial volume correction (PVC) methods are applied and evaluated. Methods We evaluated magnetic resonance imaging and 18F-AV-45 positron emission tomography data from 122 cognitively normal (CN) patients recruited at the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cortex SUVRs were obtained by using the cerebellar grey matter (CGM) (SUVRCGM) and the whole cerebellum (SUVRWC) as reference regions. The correlations between the different SUVRs and the WM uptake (WM-SUVRCGM) were studied in patients, and in a well-controlled framework based on Monte Carlo (MC) simulation. Activity maps for the MC simulation were derived from ADNI patients by using a voxel-wise iterative process (BrainViset). Ten WM uptakes covering the spectrum of WM values obtained from patient data were simulated for different patients. Three different PVC methods were tested (a) the regional voxel-based (RBV), (b) the iterative Yang (iY), and (c) a simplified analytical correction derived from our MC simulation. Results WM-SUVRCGM followed a normal distribution with an average of 1.79 and a standard deviation of 0.243 (13.6%). SUVRCGM was linearly correlated to WM-SUVRCGM (r = 0.82, linear fit slope = 0.28). SUVRWC was linearly correlated to WM-SUVRCGM (r = 0.64, linear fit slope = 0.13). Our MC results showed that these correlations are compatible with those produced by isolated spill-in effect (slopes of 0.23 and 0.11). The impact of the spill-in was mitigated by using PVC for SUVRCGM (slopes of 0.06 and 0.07 for iY and RBV), while SUVRWC showed a negative correlation with SUVRCGM after PVC. The proposed analytical correction also reduced the observed correlations when applied to patient data (r = 0.27 for SUVRCGM, r = 0.18 for SUVRWC). Conclusions There is a high correlation between WM uptake and the measured SUVR due to spill-in effect, and that this effect is reduced when including WM in the reference region. We also evaluated the performance of PVC, and we proposed an analytical correction that can be applied to preprocessed data.

Purpose Recent evidence suggests that PET imaging with amyloid-β (Aβ) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer’s disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aβ PET, contributes to AD progression remains unexplored. Methods Participants with concurrent 18F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aβ-positive cognitively impaired, and 207 Aβ-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline. Results In AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aβ, and WMH burden. Most of these associations were also observed in Aβ-negative cognitively impaired individuals. Conclusion These results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.

Background Positron emission tomography (PET) imaging has a wide applicability in oncology, cardiology and neurology. However, a major drawback when imaging very active regions such as the bladder is the spill-in effect, leading to inaccurate quantification and obscured visualisation of nearby lesions. Therefore, this study aims at investigating and correcting for the spill-in effect from high-activity regions to the surroundings as a function of activity in the hot region, lesion size and location, system resolution and application of post-filtering using a recently proposed background correction technique. This study involves analytical simulations for the digital XCAT2 phantom and validation acquiring NEMA phantom and patient data with the GE Signa PET/MR scanner. Reconstructions were done using the ordered subset expectation maximisation (OSEM) algorithm. Dedicated point-spread function (OSEM+PSF) and a recently proposed background correction (OSEM+PSF+BC) were incorporated into the reconstruction for spill-in correction. The standardised uptake values (SUV) were compared for all reconstruction algorithms. Results The simulation study revealed that lesions within 15–20 mm from the hot region were predominantly affected by the spill-in effect, leading to an increased bias and impaired lesion visualisation within the region. For OSEM, lesion SUVmax converged to the true value at low bladder activity, but as activity increased, there was an overestimation as much as 19% for proximal lesions (distance around 15–20 mm from the bladder edge) and 2–4% for distant lesions (distance larger than 20 mm from the bladder edge). As bladder SUV increases, the % SUV change for proximal lesions is about 31% and 6% for SUVmax and SUVmean, respectively, showing that the spill-in effect is more evident for the SUVmax than the SUVmean. Also, the application of post-filtering resulted in up to 65% increment in the spill-in effect around the bladder edges. For proximal lesions, PSF has no major improvement over OSEM because of the spill-in effect, coupled with the blurring effect by post-filtering. Within two voxels around the bladder, the spill-in effect in OSEM is 42% (32%), while for OSEM+PSF, it is 31% (19%), with (and without) post-filtering, respectively. But with OSEM+PSF+BC, the spill-in contribution from the bladder was relatively low (below 5%, either with or without post-filtering). These results were further validated using the NEMA phantom and patient data for which OSEM+PSF+BC showed about 70–80% spill-in reduction around the bladder edges and increased contrast-to-noise ratio up to 36% compared to OSEM and OSEM+PSF reconstructions without post-filtering. Conclusion The spill-in effect is dependent on the activity in the hot region, lesion size and location, as well as post-filtering; and this is more evident in SUVmax than SUVmean. However, the recently proposed background correction method facilitates stability in quantification and enhances the contrast in lesions with low uptake. Electronic supplementary material The online version of this article (10.1186/s40658-018-0233-8) contains supplementary material, which is available to authorized users.

Background: Although many works have supported the utility of PET radiomics, several authors have raised concerns over the robustness and replicability of the results. This study aimed to perform a systematic review on the topic of PET radiomics and the used methodologies. Methods: PubMed was searched up to 15 October 2020. Original research articles based on human data specifying at least one tumor type and PET image were included, excluding those that apply only first-order statistics and those including fewer than 20 patients. Each publication, cancer type, objective and several methodological parameters (number of patients and features, validation approach, among other things) were extracted. Results: A total of 290 studies were included. Lung (28%) and head and neck (24%) were the most studied cancers. The most common objective was prognosis/treatment response (46%), followed by diagnosis/staging (21%), tumor characterization (18%) and technical evaluations (15%). The average number of patients included was 114 (median = 71; range 20–1419), and the average number of high-order features calculated per study was 31 (median = 26, range 1–286). Conclusions: PET radiomics is a promising field, but the number of patients in most publications is insufficient, and very few papers perform in-depth validations. The role of standardization initiatives will be crucial in the upcoming years This research was partially funded by DTS17/00138 (Instituto de Salud Carlos III) and ED431F 2017/04 project (GAIN-Xunta de Galicia) SI

Background The lack of standardization of intensity normalization methods and its unknown effect on the quantification output is recognized as a major drawback for the harmonization of brain FDG-PET quantification protocols. The aim of this work is the ground truth-based evaluation of different intensity normalization methods on brain FDG-PET quantification output. Methods Realistic FDG-PET images were generated using Monte Carlo simulation from activity and attenuation maps directly derived from 25 healthy subjects (adding theoretical relative hypometabolisms on 6 regions of interest and for 5 hypometabolism levels). Single-subject statistical parametric mapping (SPM) was applied to compare each simulated FDG-PET image with a healthy database after intensity normalization based on reference regions methods such as the brain stem (RRBS), cerebellum (RRC) and the temporal lobe contralateral to the lesion (RRTL), and data-driven methods, such as proportional scaling (PS), histogram-based method (HN) and iterative versions of both methods (iPS and iHN). The performance of these methods was evaluated in terms of the recovery of the introduced theoretical hypometabolic pattern and the appearance of unspecific hypometabolic and hypermetabolic findings. Results Detected hypometabolic patterns had significantly lower volumes than the introduced hypometabolisms for all intensity normalization methods particularly for slighter reductions in metabolism . Among the intensity normalization methods, RRC and HN provided the largest recovered hypometabolic volumes, while the RRBS showed the smallest recovery. In general, data-driven methods overcame reference regions and among them, the iterative methods overcame the non-iterative ones. Unspecific hypermetabolic volumes were similar for all methods, with the exception of PS, where it became a major limitation (up to 250 cm3) for extended and intense hypometabolism. On the other hand, unspecific hypometabolism was similar far all methods, and usually solved with appropriate clustering. Conclusions Our findings showed that the inappropriate use of intensity normalization methods can provide remarkable bias in the detected hypometabolism and it represents a serious concern in terms of false positives. Based on our findings, we recommend the use of histogram-based intensity normalization methods. Reference region methods performance was equivalent to data-driven methods only when the selected reference region is large and stable.

The association between white matter hyperintensities (WMH) and amyloid accumulation over time in cognitively normal, amyloid-negative elderly people remains largely unexplored. In order to study whether baseline WMH were associated with longitudinal subthreshold amyloid accumulation, 159 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative who were amyloid-negative at baseline were examined. All the participants underwent a T1 and a Fluid-Attenuated Inversion Recovery MRI scan at baseline. Amyloid PET imaging was performed at baseline and follow-up visits in 2-year intervals for up to 8 years. Partial volume correction was applied for quantifying cortical Standardised Uptake Value Ratios (SUVR). The associations between global and regional WMH burden and amyloid accumulation were assessed using linear mixed models adjusted by demographic characteristics and baseline SUVR. Partial volume correction increased the measured annual rate of change (+2.4%) compared to that obtained from non-corrected data (+0.5%). There were no significant correlations between baseline WMHs and baseline subthreshold cortical amyloid uptake. In a longitudinal analysis, increased baseline cortical SUVR and increased baseline burden of global (p ​= ​0.006), frontal (p ​= ​0.006), and parietal WMH (p ​= ​0.003) were associated with faster amyloid accumulation. WMH-related amyloid accumulation occurred in parietal, frontal, and, to a lesser extent, cingulate cortices. These results remained unchanged after a sensitivity analysis excluding participants with the highest cortical SUVRs. This is the first study to identify a specific spatial distribution of WMH which is associated with future amyloid accumulation in cognitively normal elderly subjects without PET-detectable amyloid pathology. These findings may have important implications in prevention trials for the early identification of amyloid accumulation.

Severe allergic ocular diseases as atopic keratoconjunctivitis can induce corneal damage due to inflammatory substances released from giant papillae. Tacrolimus eye drops are one of the current therapeutic alternatives for its treatment. This work is aimed at developing and characterizing a 0.03% tacrolimus ophthalmic formulation, which was introduced in three types of vehicles (BBS, PVA and Hyaluronic Acid). For this, we have performed in vitro (stability studies) and in vivo assays (corneal permanence time measured directly by Positron Emission Tomography) of three potential formulations. Next, the best formulation was selected, and its toxicological profile and clinical effectiveness have been evaluated. The biopermanence studies (direct measurements and PET/CT) showed that the formulations with PVA and Hyaluronic Acid present more retention time on the ocular surface of rats than PBS. From the stability study, we have determined that tacrolimus with PVA in cold storage is the best option. Tacrolimus with PVA has shown lower cytotoxicity than cyclosporine at early times. On the other hand, the pilot study performed has shown significant improvements in patients, with no noticeable adverse reactions. Based on stability, biopermanence, safety and clinical effectiveness studies, we concluded that tacrolimus-PVA eye drops are a suitable candidate for its clinical application in inflammatory ophthalmology diseases.

Envisaging the possibility of using large-area plastic scintillator slabs as robust detectors for high spatial resolution muon radiography, and prior to prototype development, we study expected basic performance by Monte Carlo simulation. We present preliminary results for a scalable square footprint detector unit of $\sim 1~\hbox{m}^{2}$ , defining a representative simulation model volume of $50~\hbox{cm} \times 50~\hbox{cm}$ , with reflective surfaces and a light readout by direct coupling of 4 small PMTs (in a square arrangement) at one face of the scintillator slab. Light detection efficiency is calculated for several light collection configurations, considering different values of surface roughness, reflectivity, optical coupling index and scintillator thickness. Values maximizing photon detection have been identified. The light response function of 2.5–3.5 cm diameter PMTs for the proposed configuration has been determined. A detector intrinsic spatial resolution of the order of 1 cm is estimated for muon interactions at the center region of the detector module, using a simple centroid positioning algorithm (Anger logic).

Aim To study in detail the accuracy and repeatability of three commonly used methods for SUV estimation in solitary pulmonary nodules. Material and methods We have designed a realistic framework based on simulated FDG-PET acquisitions from an anthropomorphic activity model that included solitary pulmonary nodules (different sizes) of well-known SUV. This framework enables us to compare the SUV values obtained from the reconstructed PET images with the real SUV values. Three commonly used methods (SUV max , SUV mean and SUV 50 ) were used to estimate the tumor activity. Results Our results showed the tumor activity was overestimated using SUV max and clearly subestimated using SUV mean . Instead, the quantification of SUV 50 showed great agreement with the simulated tumor activity and only slight subestimation was found for very small lesions. On the other hand, SUV mean showed better performance than SUV 50 in terms of repeatability, providing variabilities below 5% for all tumor sizes and for injected doses as low as 111 MBq. Conclusions Our findings showed that SUV 50 provided better performance for estimating accurately tumor SUV values in pulmonary nodules, but SUV mean showed better results in terms of repeatability.

This work aimed at describing the time course of vitreous clearance through the use of positron emission tomography (PET) as a noninvasive tool for pharmacokinetic studies of intravitreal injection.The pharmacokinetic profile of intravitreal injections of molecules labeled with 18Fluorine (18F) was evaluated in adult Sprague Dawley rats by using a dedicated small-animal PET/computed tomography scanner. Different conditions were studied: three molecules radiolabeled with 18F (18F-FDG, 18F-NaF, and 18F-Choline), three volumes of intravitreal injections (7, 4, and 2 μL), and absence or presence of eye inflammation (uveitis).Our results showed that there are significant pharmacokinetic differences among the radiolabeled molecules studied but not among the injected volumes. The presence or absence of uveitis was an important factor in vitreous clearance, since the elimination of the drug was clearly increased when this condition is present.Intravitreal pharmacokinetic studies based on the use of dedicated PET imaging can be of potential interest as noninvasive tools in ophthalmic drug development in small animals.

This work is aimed at describing the utility of positron emission tomography/computed tomography (PET/CT) as a noninvasive tool for pharmacokinetic studies of biopermanence of topical ocular formulations.The corneal biopermanence of a topical ophthalmic formulation containing gellan gum and kappa carragenan (0.82% wt/vol) labeled with 18Fluorine (18F) radiotracers (18F-FDG and 18F-NaF) was evaluated by using a dedicated small-animal PET/CT, and compared with the biopermanence of an aqueous solution labeled with the same compounds. Regions of interest (ROIs) were manually drawn on the reconstructed PET images for quantifying the radioactivity concentration in the eye. The biopermanence of the formulations was determined by measuring the radioactivity concentration at different times after topical application. Additionally, cellular and ex vivo safety assays were performed to assess the safety of the performed procedures.Differences were observed in the ocular pharmacokinetics of the two formulations. After 1.5 hours of contact, 90% of the hydrogel remained in the ocular surface, while only 69% of the control solution remained. Furthermore, it was observed that flickering had a very important role in the approach of the trial. The application of 18F-FDG in the eye was neither irritating nor cytotoxic for human corneal epithelial cells.The use of small-animal PET and 18F radiotracers in ocular pharmacokinetics of ophthalmic formulations is feasible and could be a safe method for future ocular pharmacokinetic studies in humans.

The traditional lack of techniques suitable for in vivo imaging has induced a great interest in molecular imaging for preclinical research. Nevertheless, its use spreads slowly due to the difficulties in justifying the high cost of the current dedicated preclinical scanners. An alternative for lowering the costs is to repurpose old clinical gamma cameras to be used for preclinical imaging. In this paper we assess the performance of a portable device, that is, working coupled to a single-head clinical gamma camera, and we present our preliminary experience in several small animal applications. Our findings, based on phantom experiments and animal studies, provided an image quality, in terms of contrast-noise trade-off, comparable to dedicated preclinical pinhole-based scanners. We feel that our portable device offers an opportunity for recycling the widespread availability of clinical gamma cameras in nuclear medicine departments to be used in small animal SPECT imaging and we hope that it can contribute to spreading the use of preclinical imaging within institutions on tight budgets. This work was supported in part by public Fondo de Investigaciones Sanitarias ISCIII PS09/01206 and PI11/01806. P. Aguiar was awarded a public fellowship from Xunta de Galicia, POS-A/2013/001 SI

Structural Functional Synergistic Resolution Recovery (SFS-RR) is a technique that uses supplementary structural information from MR or CT to improve the spatial resolution of PET or SPECT images. This wavelet-based method may have a potential impact on the clinical decision-making of brain focal disorders such as refractory epilepsy, since it can produce images with better quantitative accuracy and enhanced detectability. In this work, a method for the iterative application of SFS-RR (iSFS-RR) was firstly developed and optimized in terms of convergence and input voxel size, and the corrected images were used for the diagnosis of 18 patients with refractory epilepsy. To this end, PET/MR images were clinically evaluated through visual inspection, atlas-based asymmetry indices (AIs) and SPM (Statistical Parametric Mapping) analysis, using uncorrected images and images corrected with SFS-RR and iSFS-RR. Our results showed that the sensitivity can be increased from 78% for uncorrected images, to 84% for SFS-RR and 94% for the proposed iSFS-RR. Thus, the proposed methodology has demonstrated the potential to improve the management of refractory epilepsy patients in the clinical routine.

An important counterpart of clinical Positron Emission Tomography (PET) for early diagnosis of neurological diseases is its low resolution. This is particularly important when evaluating diseases related to small hypometabolisms such as epilepsy. The last years, new hybrid systems combining PET with Magnetic Resonance (MR) has been increasingly used for several different clinical applications. One of the advantages of MR is the production of high spatial resolution images and a potential application of PET-MR imaging is the improvement of PET resolution using MR information. A potential advantage of resolution recovery of PET images is the enhancement of contrast delivering at the same time better detectability of small lesions or hypometabolic areas and more accurate quantification over these areas. Recently, Shidahara et al (2009) proposed a new method using wavelet transforms in order to produce PET images with higher resolution. We optimised Shidahara’s method (SFS-RR) to take into account possible shortcomings on the particular clinical datasets, and applied it to a group of patients diagnosed with refractory epilepsy. FDG-PET and MRI images were acquired sequentially and then co-registered using software tools. A complete evaluation of the PET/MR images was performed before and after the correction, including different parameters related with PET quantification, such as atlas-based metabolism asymmetry coefficients and Statistical Parametric Mapping results comparing to a database of 87 healthy subjects. Furthermore, an experienced physician analyzed the results of non-corrected and corrected images in order to evaluate improvements of detectability on a visual inspection. Clinical outcome was used as a gold standard. SFS-RR demonstrated to have a positive impact on clinical diagnosis of small hypometabolisms. New lesions were detected providing additional clinically relevant information on the visual inspection. SPM sensitivity for the detection of small lesions was increased from 70% to 90%.

Purpose: To assess the performance of two approaches to the system response matrix (SRM) calculation in pinhole single photon emission computed tomography (SPECT) reconstruction. Methods: Evaluation was performed using experimental data from a low magnification pinhole SPECT system that consisted of a rotating flat detector with a monolithic scintillator crystal. The SRM was computed following two approaches, which were based on Monte Carlo simulations (MC-SRM) and analytical techniques in combination with an experimental characterization (AE-SRM). The spatial response of the system, obtained by using the two approaches, was compared with experimental data. The effect of the MC-SRM and AE-SRM approaches on the reconstructed image was assessed in terms of image contrast, signal-to-noise ratio, image quality, and spatial resolution. To this end, acquisitions were carried out using a hot cylinder phantom (consisting of five fillable rods with diameters of 5, 4, 3, 2, and 1 mm and a uniform cylindrical chamber) and a custom-made Derenzo phantom, with center-to-center distances between adjacent rods of 1.5, 2.0, and 3.0 mm. Results: Good agreement was found for the spatial response of the system between measured data and results derived from MC-SRM and AE-SRM. Only minor differences for point sources at distances smaller than the radius of rotation and large incidence angles were found. Assessment of the effect on the reconstructed image showed a similar contrast for both approaches, with values higher than 0.9 for rod diameters greater than 1 mm and higher than 0.8 for rod diameter of 1 mm. The comparison in terms of image quality showed that all rods in the different sections of a custom-made Derenzo phantom could be distinguished. The spatial resolution (FWHM) was 0.7 mm at iteration 100 using both approaches. The SNR was lower for reconstructed images using MC-SRM than for those reconstructed using AE-SRM, indicating that AE-SRM deals better with the projection noise than MC-SRM. Conclusions: The authors' findings show that both approaches provide good solutions to the problem of calculating the SRM in pinhole SPECT reconstruction. The AE-SRM was faster to create and handle the projection noise better than MC-SRM. Nevertheless, the AE-SRM required a tedious experimental characterization of the intrinsic detector response. Creation of the MC-SRM required longer computation time and handled the projection noise worse than the AE-SRM. Nevertheless, the MC-SRM inherently incorporates extensive modeling of the system and therefore experimental characterization was not required.