PSMA-PET follow-up to assess response in patients not receiving PSMA therapy: Is there value beyond localization of disease?

Introduction: Prostate Specific Membrane Antigen Positron Emission Tomography (PSMA-PET) is routinely used for the staging of patients with prostate cancer, but data on response assessment are sparse and primarily stem from metastatic castration-resistant prostate cancer (mCRPC) patients treated with PSMA radioligand therapy. Still, follow-up PSMA-PET is employed in earlier disease stages in case of clinical suspicion of disease persistence, recurrence or progression to decide if localized or systemic treatment is indicated. Therefore, the prognostic value of PSMA-PET derived tumor volumes in earlier disease stages (i.e., hormone-sensitive prostate cancer (HSPC) and non-[177Lu]Lu-PSMA-617 (LuPSMA) therapy castration resistant prostate cancer (CRPC)) are evaluated in this manuscript. Methods: A total number of 73 patients (6 primary staging, 42 HSPC, 25 CRPC) underwent two (i.e., baseline and follow-up, median interval: 379 days) whole-body [68Ga]Ga-PSMA-11 PET/CT scans between Nov 2014 and Dec 2018. Analysis was restricted to non-LuPSMA therapy patients. PSMA-PETs were retrospectively analyzed and primary tumor, lymph node-, visceral-, and bone metastases were segmented. Body weight-adjusted organ-specific and total tumor volumes (PSMAvol: sum of PET volumes of all lesions) were measured for baseline and follow-up. PSMAvol response was calculated as the absolute difference of whole-body tumor volumes. High metastatic burden (>5 metastases), RECIP 1.0 and PSMA-PET Progression Criteria (PPP) were determined. Survival data were sourced from the cancer registry. Results: The average number of tumor lesions per patient on the initial PET examination was 10.3 (SD 28.4). At baseline, PSMAvol was strongly associated with OS (HR 3.92, p <0.001; n = 73). Likewise, response in PSMAvol was significantly associated with OS (HR 10.48, p < 0.005; n = 73). PPP achieved significance as well (HR 2.19, p <0.05, n = 73). Patients with hormone sensitive disease and poor PSMAvol response (upper quartile of PSMAvol change) in follow-up had shorter outcome (p < 0.05; n = 42). PSMAvol in bones was the most relevant parameter for OS prognostication at baseline and for response assessment (HR 31.11 p < 0.001; HR 32.27, p < 0.001; n = 73). Conclusion: PPP and response in PSMAvol were significantly associated with OS in the present heterogeneous cohort. Bone tumor volume was the relevant miTNM region for OS prognostication. Future prospective evaluation of the performance of organ specific PSMAvol in more homogeneous cohorts seems warranted.

In vivo reactive astrocyte imaging using [18F]SMBT-1 in tauopathy and familial Alzheimer's disease mouse models: A multi-tracer study.

BACKGROUND: Reactive astrocytes play an important role in the development of Alzheimer's disease and primary tauopathies. Here, we aimed to investigate the relationships between reactive astrocytes. Microgliosis and glucose metabolism with Tau and amyloid beta pathology by using multi-tracer imaging in widely used tauopathy and familial Alzheimer's disease mouse models. RESULTS: Positron emission tomography imaging using [18F]PM-PBB3 (tau), [18F]florbetapir (amyloid-beta), [18F]SMBT-1 (monoamine oxidase-B), [18F]DPA-714 (translocator protein) and [18F]fluorodeoxyglucose was carried out in 3- and 7-month-old rTg4510 tau mice, 5 × FAD familial Alzheimer's disease mice and wild-type mice. Immunofluorescence staining was performed to validate the pathological distribution in the mouse brain after in vivo imaging. We found increased regional levels of [18F]PM-PBB3, [18F]SMBT-1, and [18F]DPA-714 and hypoglucose metabolism in the brains of 7-month-old rTg4510 mice compared to age-matched wild-type mice. Increased [18F]SMBT-1 uptake was observed in the brains of 3, 7-month-old 5 × FAD mice, with elevated regional [18F]florbetapir and [18F]DPA-714 uptakes in the brains of 7-month-old 5 × FAD mice, compared to age-matched wild-type mice. Positive correlations were shown between [18F]SMBT-1 and [18F]PM-PBB3, [18F]DPA-714 and [18F]PM-PBB3 in rTg4510 mice, and between [18F]florbetapir and [18F]DPA-714 SUVRs in 5 × FAD mice. CONCLUSION: In summary, these findings provide in vivo evidence that reactive astrocytes, microglial activation, and cerebral hypoglucose metabolism are associated with tau and amyloid pathology development in animal models of tauopathy and familial Alzheimer's disease.

Tau Protein Accumulation Trajectory-Based Brain Age Prediction in the Alzheimer's Disease Continuum.

Clinical cognitive advancement within the Alzheimer's disease (AD) continuum is intimately connected with sustained accumulation of tau protein pathology. The biological brain age and its gap show great potential for pathological risk and disease severity. In the present study, we applied multivariable linear support vector regression to train a normative brain age prediction model using tau brain images. We further assessed the predicted biological brain age and its gap for patients within the AD continuum. In the AD continuum, evaluated pathologic tau binding was found in the inferior temporal, parietal-temporal junction, precuneus/posterior cingulate, dorsal frontal, occipital, and inferior-medial temporal cortices. The biological brain age gaps of patients within the AD continuum were notably higher than those of the normal controls (p < 0.0001). Significant positive correlations were observed between the brain age gap and global tau protein accumulation levels for mild cognitive impairment (r = 0.726, p < 0.001), AD (r = 0.845, p < 0.001), and AD continuum (r = 0.797, p < 0.001). The pathologic tau-based age gap was significantly linked to neuropsychological scores. The proposed pathologic tau-based biological brain age model could track the tau protein accumulation trajectory of cognitive impairment and further provide a comprehensive quantification index for the tau accumulation risk.

Increased Cerebral Level of P2X7R in a Tauopathy Mouse Model by PET Using [18F]GSK1482160.

Neuroinflammation plays an important role in Alzheimer's disease and primary tauopathies. The aim of the current study was to map [18F]GSK1482160 for imaging of purinergic P2X7R in Alzheimer's disease and primary tauopathy mouse models. Small animal PET was performed using [18F]GSK1482160 in widely used mouse models of Alzheimer's disease (APP/PS1, 5×FAD, and 3×Tg), 4-repeat tauopathy (rTg4510) mice, and age-matched wild-type mice. Increased uptake of [18F]GSK1482160 was observed in the brains of 7-month-old rTg4510 mice compared to wild-type mice and compared to 3-month-old rTg4510 mice. A positive correlation between hippocampal tau [18F]APN-1607 and [18F]GSK1482160 uptake was found in rTg4510 mice. No significant differences in the uptake of [18F]GSK1482160 was observed for APP/PS1 mice, 5×FAD mice, or 3×Tg mice. Immunofluorescence staining further indicated the distribution of P2X7Rs in the brains of 7-month-old rTg4510 mice with accumulation of tau inclusion. These findings provide in vivo imaging evidence for an increased level of P2X7R in the brains of tauopathy mice.

Prognostic Value of [99mTc]Tc-DPD Quantitative SPECT/CT in Patients with Suspected and Confirmed Amyloid Transthyretin-Related Cardiomyopathy and Preserved Left Ventricular Function.

Quantitative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid ([99mTc]Tc-DPD) SPECT may be used for risk-stratifying patients with amyloid transthyretin-related cardiomyopathy (ATTR-CM). We aimed to analyze the predictive value of quantitative [99mTc]Tc-DPD SPECT/CT in suspected and confirmed ATTR-CM according to different disease stages. Methods: The study enrolled consecutive patients with suspected ATTR-CM who were referred to a single tertiary center and underwent quantitative [99mTc]Tc-DPD SPECT/CT allowing SUVmax and SUVpeak analysis. Patients were divided into 2 groups according to left ventricular ejection fraction (LVEF) at baseline (i.e., ≥50% and <50%). Clinical, laboratory, and echocardiographic parameters and major adverse cardiac events (i.e., all-cause death, sustained ventricular tachyarrhythmia, hospitalization for heart failure, implantation of a cardioverter defibrillator) were investigated for any correlation with quantitative uptake values. Results: In total, 144 patients with suspected ATTR-CM were included in the study (98 with LVEF ≥ 50% and 46 with LVEF < 50%), of whom 99 were diagnosed with ATTR-CM (68.8%; 69 with LVEF ≥ 50% and 30 with LVEF < 50%). A myocardial SUVmax of at least 7 was predictive of major adverse cardiac events at 21.9 ± 13.0 mo of follow-up (hazard ratio, 2.875; 95% CI, 1.23-6.71; P = 0.015) in patients with suspected or confirmed ATTR-CM (global χ2 = 6.892, P = 0.02) and an LVEF of at least 50%. SUVmax was not predictive in patients with an LVEF of less than 50% and suspected or confirmed ATTR-CM. Conclusion: In patients with suspected or confirmed ATTR-CM and preserved LVEF, representing an early disease stage, quantitative [99mTc]Tc-DPD SPECT should be considered to improve early-stage risk stratification.

Characterization of tau propagation pattern and cascading hypometabolism from functional connectivity in Alzheimer's disease.

Tau pathology and its spatial propagation in Alzheimer's disease (AD) play crucial roles in the neurodegenerative cascade leading to dementia. However, the underlying mechanisms linking tau spreading to glucose metabolism remain elusive. To address this, we aimed to examine the association between pathologic tau aggregation, functional connectivity, and cascading glucose metabolism and further explore the underlying interplay mechanisms. In this prospective cohort study, we enrolled 79 participants with 18F-Florzolotau positron emission tomography (PET), 18F-fluorodeoxyglucose PET, resting-state functional, and anatomical magnetic resonance imaging (MRI) images in the hospital-based Shanghai Memory Study. We employed generalized linear regression and correlation analyses to assess the associations between Florzolotau accumulation, functional connectivity, and glucose metabolism in whole-brain and network-specific manners. Causal mediation analysis was used to evaluate whether functional connectivity mediates the association between pathologic tau and cascading glucose metabolism. We examined 22 normal controls and 57 patients with AD. In the AD group, functional connectivity was associated with Florzolotau covariance (ß = .837, r = 0.472, p < .001) and glucose covariance (ß = 1.01, r = 0.499, p < .001). Brain regions with higher tau accumulation tend to be connected to other regions with high tau accumulation through functional connectivity or metabolic connectivity. Mediation analyses further suggest that functional connectivity partially modulates the influence of tau accumulation on downstream glucose metabolism (mediation proportion: 49.9%). Pathologic tau may affect functionally connected neurons directly, triggering downstream glucose metabolism changes. This study sheds light on the intricate relationship between tau pathology, functional connectivity, and downstream glucose metabolism, providing critical insights into AD pathophysiology and potential therapeutic targets.

Pre-therapy PET-based voxel-wise dosimetry prediction by characterizing intra-organ heterogeneity in PSMA-directed radiopharmaceutical theranostics.

BACKGROUND AND OBJECTIVE: Treatment planning through the diagnostic dimension of theranostics provides insights into predicting the absorbed dose of RPT, with the potential to individualize radiation doses for enhancing treatment efficacy. However, existing studies focusing on dose prediction from diagnostic data often rely on organ-level estimations, overlooking intra-organ variations. This study aims to characterize the intra-organ theranostic heterogeneity and utilize artificial intelligence techniques to localize them, i.e. to predict voxel-wise absorbed dose map based on pre-therapy PET. METHODS: 23 patients with metastatic castration-resistant prostate cancer treated with [177Lu]Lu-PSMA I&T RPT were retrospectively included. 48 treatment cycles with pre-treatment PET imaging and at least 3 post-therapeutic SPECT/CT imaging were selected. The distribution of PET tracer and RPT dose was compared for kidney, liver and spleen, characterizing intra-organ heterogeneity differences. Pharmacokinetic simulations were performed to enhance the understanding of the correlation. Two strategies were explored for pre-therapy voxel-wise dosimetry prediction: (1) organ-dose guided direct projection; (2) deep learning (DL)-based distribution prediction. Physical metrics, dose volume histogram (DVH) analysis, and identity plots were applied to investigate the predicted absorbed dose map. RESULTS: Inconsistent intra-organ patterns emerged between PET imaging and dose map, with moderate correlations existing in the kidney (r = 0.77), liver (r = 0.5), and spleen (r = 0.58) (P < 0.025). Simulation results indicated the intra-organ pharmacokinetic heterogeneity might explain this inconsistency. The DL-based method achieved a lower average voxel-wise normalized root mean squared error of 0.79 ± 0.27%, regarding to ground-truth dose map, outperforming the organ-dose guided projection (1.11 ± 0.57%) (P < 0.05). DVH analysis demonstrated good prediction accuracy (R2 = 0.92 for kidney). The DL model improved the mean slope of fitting lines in identity plots (199% for liver), when compared to the theoretical optimal results of the organ-dose approach. CONCLUSION: Our results demonstrated the intra-organ heterogeneity of pharmacokinetics may complicate pre-therapy dosimetry prediction. DL has the potential to bridge this gap for pre-therapy prediction of voxel-wise heterogeneous dose map.

Individual cerebellar metabolic connectome in patients with MTLE and NTLE associated with surgical prognosis.

PURPOSE: This study aimed to comprehensively explore the different metabolic connectivity topological changes in MTLE and NTLE, as well as their association with surgical outcomes. METHODS: This study enrolled a cohort of patients with intractable MTLE and NTLE. Each individual's metabolic connectome, as determined by Kullback-Leibler divergence similarity estimation for the [18F]FDG PET image, was employed to conduct a comprehensive analysis of the cerebral metabolic network. Alterations in network connectivity were assessed by extracting and evaluating the strength of edge and weighted connectivity. By utilizing these two connectivity strength metrics with the cerebellum, we explored the network properties of connectivity and its association with prognosis in surgical patients. RESULTS: Both MTLE and NTLE patients exhibited substantial alterations in the connectivity of the metabolic network at the edge and nodal levels (p < 0.01, FDR corrected). The key disparity between MTLE and NTLE was observed in the cerebellum. In MTLE, there was a predominance of increased connectivity strength in the cerebellum. Whereas, a decrease in cerebellar connectivity was identified in NTLE. It was found that in MTLE, higher edge connectivity and weighted connectivity strength in the contralateral cerebellar hemisphere correlated with improved surgical outcomes. Conversely, in NTLE, a higher edge metabolic connectivity strength in the ipsilateral cerebellar hemisphere suggested a worse surgical prognosis. CONCLUSION: The cerebellum exhibits distinct topological characteristics in the metabolic networks between MTLE and NTLE. The hyper- or hypo-metabolic connectivity in the cerebellum may be a prognostic biomarker of surgical prognosis, which might aid in therapeutic decision-making for TLE individuals.

Automated extraction of the arterial input function from brain images for parametric PET studies.

BACKGROUND: Accurate measurement of the arterial input function (AIF) is crucial for parametric PET studies, but the AIF is commonly derived from invasive arterial blood sampling. It is possible to use an image-derived input function (IDIF) obtained by imaging a large blood pool, but IDIF measurement in PET brain studies performed on standard field of view scanners is challenging due to lack of a large blood pool in the field-of-view. Here we describe a novel automated approach to estimate the AIF from brain images. RESULTS: Total body 18F-FDG PET data from 12 subjects were split into a model adjustment group (n = 6) and a validation group (n = 6). We developed an AIF estimation framework using wavelet-based methods and unsupervised machine learning to distinguish arterial and venous activity curves, compared to the IDIF from the descending aorta. All of the automatically extracted AIFs in the validation group had similar shape to the IDIF derived from the descending aorta IDIF. The average area under the curve error and normalised root mean square error across validation data were - 1.59 ± 2.93% and 0.17 ± 0.07. CONCLUSIONS: Our automated AIF framework accurately estimates the AIF from brain images. It reduces operator-dependence, and could facilitate the clinical adoption of parametric PET.

Dose Reduction in Pediatric Oncology Patients with Delayed Total-Body [18F]FDG PET/CT.

Our aim was to define a lower limit of reduced injected activity in delayed [18F]FDG total-body (TB) PET/CT in pediatric oncology patients. Methods: In this single-center prospective study, children were scanned for 20 min with TB PET/CT, 120 min after intravenous administration of a 4.07 ± 0.49 MBq/kg dose of [18F]FDG. Five randomly subsampled low-count reconstructions were generated using », ⅛, [Formula: see text], and [Formula: see text] of the counts in the full-dose list-mode reference standard acquisition (20 min), to simulate dose reduction. For the 2 lowest-count reconstructions, smoothing was applied. Background uptake was measured with volumes of interest placed on the ascending aorta, right liver lobe, and third lumbar vertebra body (L3). Tumor lesions were segmented using a 40% isocontour volume-of-interest approach. Signal-to-noise ratio, tumor-to-background ratio, and contrast-to-noise ratio were calculated. Three physicians identified malignant lesions independently and assessed the image quality using a 5-point Likert scale. Results: In total, 113 malignant lesions were identified in 18 patients, who met the inclusion criteria. Of these lesions, 87.6% were quantifiable. Liver SUVmean did not change significantly, whereas a lower signal-to-noise ratio was observed in all low-count reconstructions compared with the reference standard (P < 0.0001) because of higher noise rates. Tumor uptake (SUVmax), tumor-to-background ratio, and total lesion count were significantly lower in the reconstructions with [Formula: see text] and [Formula: see text] of the counts of the reference standard (P < 0.001). Contrast-to-noise ratio and clinical image quality were significantly lower in all low-count reconstructions than with the reference standard. Conclusion: Dose reduction for delayed [18F]FDG TB PET/CT imaging in children is possible without loss of image quality or lesion conspicuity. However, our results indicate that to maintain comparable tumor uptake and lesion conspicuity, PET centers should not reduce the injected [18F]FDG activity below 0.5 MBq/kg when using TB PET/CT in pediatric imaging at 120 min after injection.

Mapping 18F-FDG Kinetics Together with Patient-Specific Bootstrap Assessment of Uncertainties: An Illustration with Data from a PET/CT Scanner with a Long Axial Field of View.

The purpose of this study was to examine a nonparametric approach to mapping kinetic parameters and their uncertainties with data from the emerging generation of dynamic whole-body PET/CT scanners. Methods: Dynamic PET 18F-FDG data from a set of 24 cancer patients studied on a long-axial-field-of-view PET/CT scanner were considered. Kinetics were mapped using a nonparametric residue mapping (NPRM) technique. Uncertainties were evaluated using an image-based bootstrapping methodology. Kinetics and bootstrap-derived uncertainties are reported for voxels, maximum-intensity projections, and volumes of interest (VOIs) corresponding to several key organs and lesions. Comparisons between NPRM and standard 2-compartment (2C) modeling of VOI kinetics are carefully examined. Results: NPRM-generated kinetic maps were of good quality and well aligned with vascular and metabolic 18F-FDG patterns, reasonable for the range of VOIs considered. On a single 3.2-GHz processor, the specification of the bootstrapping model took 140 min; individual bootstrap replicates required 80 min each. VOI time-course data were much more accurately represented, particularly in the early time course, by NPRM than by 2C modeling constructs, and improvements in fit were statistically highly significant. Although 18F-FDG flux values evaluated by NPRM and 2C modeling were generally similar, significant deviations between vascular blood and distribution volume estimates were found. The bootstrap enables the assessment of quite complex summaries of mapped kinetics. This is illustrated with maximum-intensity maps of kinetics and their uncertainties. Conclusion: NPRM kinetics combined with image-domain bootstrapping is practical with large whole-body dynamic 18F-FDG datasets. The information provided by bootstrapping could support more sophisticated uses of PET biomarkers used in clinical decision-making for the individual patient.

Relationship Between Reactive Astrocytes, by [18F]SMBT-1 Imaging, with Amyloid-Beta, Tau, Glucose Metabolism, and TSPO in Mouse Models of Alzheimer's Disease.

Reactive astrocytes play an important role in the development of Alzheimer's disease (AD). Here, we aimed to investigate the temporospatial relationships among monoamine oxidase-B, tau and amyloid-ß (Aß), translocator protein, and glucose metabolism by using multitracer imaging in AD transgenic mouse models. Positron emission tomography (PET) imaging with [18F]SMBT-1 (monoamine oxidase-B), [18F]florbetapir (Aß), [18F]PM-PBB3 (tau), [18F]fluorodeoxyglucose (FDG), and [18F]DPA-714 (translocator protein) was carried out in 5- and 10-month-old APP/PS1, 11-month-old 3×Tg mice, and aged-matched wild-type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as the reference region. Immunofluorescence staining was performed on mouse brain tissue slices. [18F]SMBT-1 and [18F]florbetapir SUVRs were greater in the cortex and hippocampus of 10-month-old APP/PS1 mice than in those of 5-month-old APP/PS1 mice and wild-type mice. No significant difference in the regional [18F]FDG or [18F]DPA-714 SUVRs was observed in the brains of 5- or 10-month-old APP/PS1 mice or wild-type mice. No significant difference in the SUVRs of any tracer was observed between 11-month-old 3×Tg mice and age-matched wild-type mice. A positive correlation between the SUVRs of [18F]florbetapir and [18F]DPA-714 in the cortex and hippocampus was observed among the transgenic mice. Immunostaining validated the distribution of MAO-B and limited Aß and tau pathology in 11-month-old 3×Tg mice; and Aß deposits in brain tissue from 10-month-old APP/PS1 mice. In summary, these findings provide in vivo evidence that an increase in astrocyte [18F]SMBT-1 accompanies Aß accumulation in APP/PS1 models of AD amyloidosis.

Detection of individual brain tau deposition in Alzheimer's disease based on latent feature-enhanced generative adversarial network.

OBJECTIVE: The conventional methods for interpreting tau PET imaging in Alzheimer's disease (AD), including visual assessment and semi-quantitative analysis of fixed hallmark regions, are insensitive to detect individual small lesions because of the spatiotemporal neuropathology's heterogeneity. In this study, we proposed a latent feature-enhanced generative adversarial network model for the automatic extraction of individual brain tau deposition regions. METHODS: The latent feature-enhanced generative adversarial network we propose can learn the distribution characteristics of tau PET images of cognitively normal individuals and output the abnormal distribution regions of patients. This model was trained and validated using 1131 tau PET images from multiple centres (with distinct races, i.e., Caucasian and Mongoloid) with different tau PET ligands. The overall quality of synthetic imaging was evaluated using structural similarity (SSIM), peak signal to noise ratio (PSNR), and mean square error (MSE). The model was compared to the fixed templates method for diagnosing and predicting AD. RESULTS: The reconstructed images archived good quality, with SSIM = 0.967 ± 0.008, PSNR = 31.377 ± 3.633, and MSE = 0.0011 ± 0.0007 in the independent test set. The model showed higher classification accuracy (AUC = 0.843, 95 % CI = 0.796-0.890) and stronger correlation with clinical scales (r = 0.508, P < 0.0001). The model also achieved superior predictive performance in the survival analysis of cognitive decline, with a higher hazard ratio: 3.662, P < 0.001. INTERPRETATION: The LFGAN4Tau model presents a promising new approach for more accurate detection of individualized tau deposition. Its robustness across tracers and races makes it a potentially reliable diagnostic tool for AD in practice.

Reduced SV2A and GABAA receptor levels in the brains of type 2 diabetic rats revealed by [18F]SDM-8 and [18F]flumazenil PET.

PURPOSE: Type 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease. Synaptic impairment and protein aggregates have been reported in the brains of T2DM models. Here, we assessed whether neurodegenerative changes in synaptic vesicle 2 A (SV2A), γ-aminobutyric acid type A (GABAA) receptor, amyloid-ß, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats. METHODS: Positron emission tomography (PET) using [18F]SDM-8 (SV2A), [18F]flumazenil (GABAA receptor), [18F]florbetapir (amyloid-ß), [18F]PM-PBB3 (tau), and [18F]FPS-ZM1 (RAGE) was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and SpragueDawley (SD) rats. Immunofluorescence staining, Thioflavin S staining, proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats. RESULTS: Reduced cortical [18F]SDM-8 uptake and cortical and hippocampal [18F]flumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. The regional uptake of [18F]florbetapir and [18F]PM-PBB3 was comparable in the brains of 12-month-old ZDF and SD rats. Immunofluorescence staining revealed Thioflavin S-negative, phospho-tau-positive inclusions in the cortex and hypothalamus in the brains of ZDF rats and the absence of amyloid-beta deposits. The level of GABAA receptors was lower in the cortex of ZDF rats than SD rats. Proteomic analysis further demonstrated that, compared with SD rats, synaptic-related proteins and pathways were downregulated in the hippocampus of ZDF rats. CONCLUSION: These findings provide in vivo evidence for regional reductions in SV2A and GABAA receptor levels in the brains of aged T2DM ZDF rats.

90Y post-radioembolization clinical assessment with whole-body Biograph Vision Quadra PET/CT: image quality, tumor, liver and lung dosimetry.

PURPOSE: Evaluation of 90Y liver radioembolization post-treatment clinical data using a whole-body Biograph Vision Quadra PET/CT to investigate the potential of protocol optimization in terms of scan time and dosimetry. METHODS: 17 patients with hepatocellular carcinoma with median (IQR) injected activity 2393 (1348-3298) MBq were included. Pre-treatment dosimetry plan was based on 99mTc-MAA SPECT/CT with Simplicit90Y™ and post-treatment validation with Quadra using Simplicit90Y™ and HERMIA independently. Regarding the image analysis, mean and peak SNR, the coefficient of variation (COV) and lesion-to-background ratio (LBR) were evaluated. For the post-treatment dosimetry validation, the mean tumor, whole liver and lung absorbed dose evaluation was performed using Simplicit90Y and HERMES. Images were reconstructed with 20-, 15-, 10-, 5- and 1- min sinograms with 2, 4, 6 and 8 iterations. Wilcoxon signed rank test was used to show statistical significance (p < 0.05). RESULTS: There was no difference of statistical significance between 20- and 5- min reconstructed times for the peak SNR, COV and LBR. In addition, there was no difference of statistical significance between 20- and 1- min reconstructed times for all dosimetry metrics. Lung dosimetry showed consistently lower values than the expected. Tumor absorbed dose based on Simplicit90Y™ was similar to the expected while HERMES consistently underestimated significantly the measured tumor absorbed dose. Finally, there was no difference of statistical significance between expected and measured tumor, whole liver and lung dose for all reconstruction times. CONCLUSION: In this study we evaluated, in terms of image quality and dosimetry, whole-body PET clinical images of patients after having been treated with 90Y microspheres radioembolization for liver cancer. Compared to the 20-min standard scan, the simulated 5-min reconstructed images provided equal image peak SNR and noise behavior, while performing also similarly for post-treatment dosimetry of tumor, whole liver and lung absorbed doses.

FDG imaging with long-axial field-of-view PET/CT in patients with high blood glucose-a matched pair analysis.

PURPOSE: High blood glucose (hBG) in patients undergoing [18F]FDG PET/CT scans often results in rescheduling the examination, which may lead to clinical delay for the patient and decrease productivity for the department. The aim of this study was to evaluate whether long-axial field-of-view (LAFOV) PET/CT can minimize the effect of altered bio-distribution in hBG patients and is able to provide diagnostic image quality in hBG situations. MATERIALS AND METHODS: Oncologic patients with elevated blood glucose (≥ 8.0 mmol/l) and normal blood glucose (< 8.0 mmol/l, nBG) levels were matched for tumor entity, gender, age, and BMI. hBG patients were further subdivided into two groups (BG 8-11 mmol/l and BG > 11 mmol/l). Tracer uptake in the liver, muscle, and tumor was evaluated. Furthermore, image quality was compared between long acquisitions (ultra-high sensitivity mode, 360 s) on a LAFOV PET/CT and routine acquisitions equivalent to a short-axial field-of-view scanner (simulated (sSAFOV), obtained with high sensitivity mode, 120 s). Tumor-to-background ratio (TBR) and contrast-to-noise ratio (CNR) were used as the main image quality criteria. RESULTS: Thirty-one hBG patients met the inclusion criteria and were matched with 31 nBG patients. Overall, liver uptake was significantly higher in hBG patients (SUVmean, 3.07 ± 0.41 vs. 2.37 ± 0.33; p = 0.03), and brain uptake was significantly lower (SUVmax, 7.58 ± 0.74 vs. 13.38 ± 3.94; p < 0.001), whereas muscle (shoulder/gluteal) uptake showed no statistically significant difference. Tumor uptake was lower in hBG patients, resulting in a significantly lower TBR in the hBG cohort (3.48 ± 0.74 vs. 5.29 ± 1.48, p < 0.001). CNR was higher in nBG compared to hBG patients (12.17 ± 4.86 vs. 23.31 ± 12.22, p < 0.001). However, subgroup analysis of nBG 8-11 mmol/l on sSAFOV PET/CT compared to hBG (> 11 mmol/l) patients examined with LAFOV PET/CT showed no statistical significant difference in CNR (19.84 ± 8.40 vs. 17.79 ± 9.3, p = 0.08). CONCLUSION: While elevated blood glucose (> 11 mmol) negatively affected TBR and CNR in our cohort, the images from a LAFOV PET-scanner had comparable CNR to PET-images acquired from nBG patients using sSAFOV PET/CT. Therefore, we argue that oncologic patients with increased blood sugar levels might be imaged safely with LAFOV PET/CT when rescheduling is not feasible.

Internal dosimetry study of [82Rb]Cl using a long axial field-of-view PET/CT.

PURPOSE: Long axial field-of-view (LAFOV) positron emission tomography (PET) systems allow to image all major organs with one bed position, which is particularly useful for acquiring whole-body dynamic data using short-lived radioisotopes like 82Rb. METHODS: We determined the absorbed dose in target organs of three subjects (29, 40, and 57 years old) using two different methods, i.e., MIRD and voxel dosimetry. The subjects were injected with 407.0 to 419.61 MBq of [82Rb]Cl and were scanned dynamically for 7 min with a LAFOV PET/CT scanner. RESULTS: Using the MIRD formalism and voxel dosimetry, the absorbed dose ranged from 1.84 to 2.78 µGy/MBq (1.57 to 3.92 µGy/MBq for voxel dosimetry) for the heart wall, 2.76 to 5.73 µGy/MBq (3.22 to 5.37 µGy/MBq for voxel dosimetry) for the kidneys, and 0.94 to 1.88 µGy/MBq (0.98 to 1.92 µGy/MBq for voxel dosimetry) for the lungs. The total body effective dose lied between 0.50 and 0.76 µSv/MBq. CONCLUSION: Our study suggests that the radiation dose associated with [82Rb]Cl PET/CT can be assessed by means of dynamic LAFOV PET and that it is lower compared to literature values.

Towards quality management of artificial intelligence systems for medical applications.

The use of artificial intelligence systems in clinical routine is still hampered by the necessity of a medical device certification and/or by the difficulty of implementing these systems in a clinic's quality management system. In this context, the key questions for a user are how to ensure robust model predictions and how to appraise the quality of a model's results on a regular basis. In this paper we discuss some conceptual foundation for a clinical implementation of a machine learning system and argue that both vendors and users should take certain responsibilities, as is already common practice for high-risk medical equipment. We propose the methodology from AAPM Task Group 100 report No. 283 as a conceptual framework for developing risk-driven a quality management program for a clinical process that encompasses a machine learning system. This is illustrated with an example of a clinical workflow. Our analysis shows how the risk evaluation in this framework can accommodate artificial intelligence based systems independently of their robustness evaluation or the user's in-house expertise. In particular, we highlight how the degree of interpretability of a machine learning system can be systematically accounted for within the risk evaluation and in the development of a quality management system.

Triggered Seizures for Ictal SPECT Imaging: A Case Series and Feasibility Study.

Ictal SPECT is an informative seizure imaging technique to tailor epilepsy surgery. However, capturing the onset of unpredictable seizures is a medical and logistic challenge. Here, we sought to image planned seizures triggered by direct stimulation of epileptic networks via stereotactic electroencephalography (sEEG) electrodes. Methods: In this case series of 3 adult participants with left temporal epilepsy, we identified and stimulated sEEG contacts able to trigger patient-typical seizures. We administered 99mTc-HMPAO within 12 s of ictal onset and acquired SPECT images within 40 min without any adverse events. Results: Ictal hyperperfusion maps partially overlapped concomitant sEEG seizure activity. In both participants known for periictal aphasia, SPECT imaging revealed hyperperfusion in the speech cortex lacking sEEG coverage. Conclusion: Triggering of seizures for ictal SPECT complements discrete sEEG sampling with spatially complete images of early seizure propagation. This readily implementable method revives interest in seizure imaging to guide resective epilepsy surgery.

Phantom study for 90Y liver radioembolization dosimetry with a long axial field-of-view PET/CT.

PURPOSE: The physical properties of yttrium-90 (90Y) allow for imaging with positron emission tomography/computed tomography (PET/CT). The increased sensitivity of long axial field-of-view (LAFOV) PET/CT scanners possibly allows to overcome the small branching ratio for positron production from 90Y decays and to improve for the post-treatment dosimetry of 90Y of selective internal radiation therapy. METHODS: For the challenging case of an image quality body phantom, we compare a full Monte Carlo (MC) dose calculation with the results from the two commercial software packages Simplicit90Y and Hermes. The voxel dosimetry module of Hermes relies on the 90Y images taken with a LAFOV PET/CT, while the MC and Simplicit90Y dose calculations are image independent. RESULTS: The resulting doses from the MC calculation and Simplicit90Y agree well within the error margins. The image-based dose calculation with Hermes, however, consistently underestimates the dose. This is due to the mismatch of the activity distribution in the PET images and the size of the volume of interest. We found that only for the smallest phantom sphere there is a statistically significant dependence of the Hermes dose on the image reconstruction parameters and scan time. CONCLUSION: Our study shows that Simplicit90Y's local deposition model can provide a reliable dose estimate. On the other hand, the image based dose calculation suffers from the suboptimal reconstruction of the 90Y distribution in small structures.