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The purpose of this study was to determine the inter- and intra-observer variability in 99mtechnetium-pyrophosphate (99mTc-PYP) scan interpretation for diagnosis of transthyretin cardiac amyloidosis (ATTR). Our study cohort comprised 100 consecutive subjects referred for 99mTc-PYP imaging based on clinical suspicion of ATTR cardiac amyloidosis. Myocardial 99mTc-PYP uptake was assessed by both visual (comparison of myocardial to rib uptake) and semi-quantitative (heart-to-contralateral lung uptake ratio, H:CL) methods. Twenty scans were analyzed twice, at least 48 hours apart, by each of two independent observers. Patients with visual scores of ≥ 2 on planar imaging as well as myocardial uptake on SPECT/CT were classified as ATTR positive. Diagnosis of ATTR by visual 99mTc-PYP grade was perfectly reproducible [concordance: positive and negative scans 100% (53/53 and 47/47, respectively). Both inter- and intra-observer correlations for H:CL ratio (r2 = 0.90, 0.99 (Observer 1) and 0.98 (Observer 2), respectively) and repeatability values on Bland–Altman plots were excellent. The coefficient of variation (%) for Observers 1 and 2 was 3.21 (2.14 to 4.29) and 7.49 (4.95 to 10.09), respectively. In addition, there was 100% concordance in positive and negative scan interpretation by visual grading between novice CV imagers (< 3 years’ experience) and an experienced CV imager (10 years’ experience). This study showed excellent inter-observer reproducibility and intra-observer repeatability of 99mTc-PYP visual scan interpretation and H:CL ratio for diagnosis of cardiac ATTR amyloidosis. Cardiac ATTR amyloidosis can be diagnosed reliably using 99mTc-PYP SPECT/CT by novice and experienced CV imagers.

The primary aims of this study were to determine the correlation between absolute quantitative 99mTc-pyrophosphate metrics and traditional measures of cardiac amyloid burden and to measure the intraobserver repeatability of the quantitative metrics. Methods: We studied 72 patients who underwent 99mTc-pyrophosphate SPECT/CT using a novel general-purpose cadmium-zinc-telluride-based SPECT/CT system. The clinical standard for these studies is visual grading (with grades of 0, 1, 2, and 3 indicating myocardial uptake absent, less than rib uptake, equal to rib uptake, or more than rib uptake, respectively). A visual grade of 2 or more was considered positive. For 72 patients, SUVmax, SUVmean, cardiac amyloid activity (CAA; i.e., SUVmean × left ventricular [LV] volume), and percentage injected dose (%ID) were calculated, and visual grading was performed. The correlation was determined between the 4 quantitative metrics or visual grades and the LV mass index (LVMI) (indexed to body surface area on echocardiography, 67 patients). For a subset of 11 patients, the correlation was determined between the visual or quantitative metrics and the extracellular volume (ECV) on cardiac MRI. Normal linear regression was used to compare the standardized association of each of the 4 quantitative metrics with LVMI, as a surrogate for amyloid burden. Receiver-operating-characteristic curve analysis was used to determine the diagnostic accuracy of quantitative metrics, using visual grading as the reference standard. The intraobserver repeatability of generating quantitative metrics was also determined. Results: All 4 quantitative metrics were highly accurate, with an area under the receiver-operating-characteristic curve of more than 0.96 for diagnosis of transthyretin cardiac amyloidosis. SUVmax, SUVmean, CAA, %ID, and visual grade were moderately positively correlated with LVMI (r = 0.485 for %ID) and strongly positively correlated, albeit in a small cohort, with ECV (r = 0.873, SUVmax). Intraobserver repeatability was excellent, with less than a 2% coefficient of variation for SUVmax, %ID, and CAA and 3.8% for SUVmean All 4 quantitative metrics had a standardized effect of more than 0.324 on LVMI; the largest standardized effect was 0.485, for %ID. Conclusion: In this first (to our knowledge) study of 99mTc-pyrophosphate cardiac imaging using a novel cadmium-zinc-telluride SPECT/CT scanner, SUVmax, SUVmean, CAA, and %ID measured by absolute quantitation of 99mTc-pyrophosphate were moderately correlated with LVMI and strongly correlated, albeit in a small cohort, with ECV. The intraobserver repeatability of generating the quantitative metrics was excellent.

Objective Early detection and proper management of mental illness can help to prevent severe deterioration. However, with limited financial and human resources of community mental health services, it is not practical to carry out all conventional screening tools simultaneously. In this study, we aimed to develop and validate a brief but comprehensive screening questionnaire for four common mental illnesses of the elderly.Methods The brief screening for four mental illnesses of elderly (BS4MI-elderly) is a 14-item binary response questionnaire that covers dementia, depressive disorder, sleep disorder, and hwa-byung. To test validity, we compared conventional scale scores for three groups of participants classified using the BS4MI-elderly. The sensitivity, specificity, predictive value of positive test, likelihood ratio of positive test and internal consistency of the BS4MI-elderly were assessed. Finally, a correlation analysis between the BS4MI-elderly and general mental health scales was conducted.Results A total of 254 participants aged over 65 years were recruited. The BS4MI-elderly showed moderate to high sensitivity for the test that distinguishes the normal group from the risk and disorder groups (dementia: 0.61, depressive disorder: 0.88, sleep disorder: 0.85, hwa-byung: 0.94) and high specificity for the test that distinguishes the disorder group from the normal and risk groups (dementia: 0.91, depressive disorder: 0.93, hwa-byung: 0.84, sleep disorder: 0.84). The BS4MI-elderly also exhibited good internal consistency and significant correlations with general mental health scales.Conclusion The BS4MI-elderly, a brief but comprehensive screening tool, could be a useful instrument for screening the elderly in community mental health services.

The clinical diagnosis of pulmonary involvement in individuals with systemic AL amyloidosis remains challenging. [18F]florbetapir imaging has previously identified AL amyloid deposits in the heart and extra-cardiac organs. The aim of this study is to determine quantitative [18F]florbetapir pulmonary kinetics to identify pulmonary involvement in individuals with systemic AL amyloidosis. We prospectively enrolled 58 subjects with biopsy-proven AL amyloidosis and 9 control subjects (5 without amyloidosis and 4 with ATTR cardiac amyloidosis). Pulmonary [18F]florbetapir uptake was evaluated visually and quantified as distribution volume of specific binding (Vs) derived from compartmental analysis and simpler semiquantitative metrics of maximum standardized uptake values (SUVmax), retention index (RI), and target-to-blood ratio (TBR). On visual analysis, pulmonary tracer uptake was absent in most AL subjects (40/58, 69%); 12% (7/58) of AL subjects demonstrated intense bilateral homogeneous tracer uptake. In this group, compared to the control group, Vs (median Vs 30-fold higher, 9.79 vs. 0.26, p 3-fold higher Vs compared to the control group (median 0.99 vs. 0.26, p < 0.001). Vs was independently related to left ventricular SUVmax, a marker of cardiac AL deposition, but not to ejection fraction, a marker of cardiac dysfunction. Also, intense [18F]florbetapir lung uptake was not related to [11C]acetate lung uptake, suggesting that intense [18F]florbetapir lung uptake represents AL amyloidosis rather than heart failure. [18F]florbetapir PET/CT offers the potential to noninvasively identify pulmonary AL amyloidosis, and its clinical relevance warrants further study.

This study sought to test whether relative apical sparing (RELAPS) of left ventricular (LV) longitudinal strain (LS) in cardiac amyloidosis (CA) is explained by regional differences in markers of amyloid burden (Further knowledge of the pathophysiological basis for RELAPS can help understand the adverse outcomes associated with apical LS impairment.This was a prospective study of 32 subjects (age 62 ± 7 years; 50% males) with light chain CA. All subjects underwent two-dimensional echocardiography for LS estimation andThere was a significant base-to-apex gradient in LS (-7.4 ± 3.2% vs. -8.6 ± 4.0% vs. -20.8 ± 6.6%; p 0.0001), maximal LV wall thickness (15.7 ± 1.9 cm vs. 15.4 ± 2.9 cm vs. 10.1 ± 2.4 cm; p 0.0001), and LV mass (74.8 ± 21.2 g vs. 60.8 ± 17.3 g vs. 23.4 ± 6.2 g; p 0.0001). In contrast, florbetapir RI (0.089 ± 0.03 μmol/min/g vs. 0.097 ± 0.03 μmol/min/g vs. 0.085 ± 0.03 μmol/min/g; p = 0.45) and ECV (0.53 ± 0.08 vs. 0.49 ± 0.08 vs. 0.49 ± 0.07; p = 0.15) showed no significant base-to-apex gradient in the tissue concentration or proportion of amyloid infiltration, whereas markers of total amyloid load, such as total florbetapir binding (3.4 ± 1.7 μmol/min vs. 2.8 ± 1.5 μmol/min vs. 0.93 ± 0.49 μmol/min; p 0.0001) and extracellular LV mass (40.0 ± 15.6 g vs. 30.2 ± 10.9 g vs. 11.6 ± 3.9 g; p 0.0001), did show a marked base-to-apex gradient.Segmental differences in the distribution of the total amyloid mass, rather than the proportion of amyloid deposits, appear to explain the marked regional differences in LS in CA. Although these 2 matrices are clearly related concepts, they should not be used interchangeably.

BACKGROUND: Gallium-68 Dotatate binds preferentially to somatostatin receptor (sstr) subtype-2 (sstr-2) on inflammatory cells. We aimed at investigating the potential clinical use of sstr-targeted imaging for the detection of myocardial inflammation. METHODS: 13 patients with suspected cardiac sarcoidosis (CS) based on clinical history and myocardial uptake on recent fluorine-18 fluorodeoxyglucose (FDG) PET, were enrolled to undergo Dotatate PET after FDG PET (median time 37 days [IQR 25 – 55]). Additionally, we investigated ex-vivo the immunohistochemistry expression of sstr-2 in 3 explanted sarcoid hearts. RESULTS: All FDG scans showed cardiac uptake (focal/multifocal = 6, focal on diffuse/heterogeneous = 7), and 46% (n=6) extra-cardiac uptake (mediastinal/hilar). In comparison, Dotatate scans showed definite abnormal cardiac uptake (focal/multifocal) in 4 patients, probably abnormal (heterogenous/patchy) in 3, and negative uptake in 6 cases. Similarly, 6 patients had increased mediastinal/hilar Dotatate uptake. Overall concordance of FDG and Dotatate uptake was 54% in the heart and 100% for thoracic nodal activity. Quantitatively, FDG maximum standardized uptake value was 5.0 times [3.8 – 7.1] higher in the heart, but only 2.25 times [1.7 – 3.0; P=0.019] higher in thoracic nodes relative to Dotatate. Ex-vivo, sstr-2 immunostaining was weakly seen within well-formed granulomas in all 3 examined sarcoid heart specimens with no significant staining of background myocardium or normal myocardium. CONCLUSION: Our preliminary data suggests that, compared to FDG imaging, somatostatin receptor-targeted imaging may be less sensitive for the detection of myocardial inflammation, but comparable for detecting extra-cardiac inflammation.

Purpose This study was to develop a convolutional neural network (CNN) model with a residual learning framework to predict the full-time 18F-florbetaben (18F-FBB) PET/CT images from corresponding short-time scans. Methods In this retrospective study, we enrolled 22 cognitively normal subjects, 20 patients with mild cognitive impairment, and 42 patients with Alzheimer disease. Twenty minutes of list-mode PET/CT data were acquired and reconstructed as the ground-truth images. The short-time scans were made in either 1, 2, 3, 4, or 5 minutes. The CNN with a residual learning framework was implemented to predict the ground-truth images of 18F-FBB PET/CT using short-time scans with either a single-slice or a 3-slice input layer. Model performance was evaluated by quantitative and qualitative analyses. Additionally, we quantified the amyloid load in the ground-truth and predicted images using the SUV ratio. Results On quantitative analyses, with increasing scan time, the normalized root-mean-squared error and the SUV ratio differences between predicted and ground-truth images gradually decreased, and the peak signal-to-noise ratio increased. On qualitative analysis, the predicted images from the 3-slice CNN model showed better image quality than those from the single-slice model. The 3-slice CNN model with a short-time scan of at least 2 minutes achieved comparable, quantitative prediction of full-time 18F-FBB PET/CT images, with adequate to excellent image quality. Conclusions The 3-slice CNN model with a residual learning framework is promising for the prediction of full-time 18F-FBB PET/CT images from short-time scans.

ObjectiveThe goal of our study is to assess the role of microglial activation in MS-associated fatigue (MSAF) using [F-18]PBR06-PET.MethodsFatigue severity was measured using the Modified Fatigue Impact Scale (MFIS) in 12 subjects with MS (7 relapsing-remitting and 5 secondary progressive) and 10 healthy control participants who underwent [F-18]PBR06-PET. The MFIS provides a total fatigue score as well as physical, cognitive, and psychosocial fatigue subscale scores. Standardized Uptake Value (SUV) 60–90 minute frame PET maps were coregistered to 3T MRI. Voxel-by-voxel analysis using Statistical Parametric Mapping and atlas-based regional analyses were performed. SUV ratios (SUVRs) were global brain normalized.ResultsPeak voxel-based level of significance for correlation between total fatigue score and PET uptake was localized to the right substantia nigra (T-score 4.67, p = 0.001). Similarly, SUVRs derived from atlas-based segmentation of the substantia nigra showed significant correlation with MFIS (r = 0.76, p = 0.004). On multiple regression, the right substantia nigra was an independent predictor of total MFIS (p = 0.02) and cognitive MFIS subscale values (p = 0.007), after adjustment for age, disability, and depression. Several additional areas of significant correlations with fatigue scores were identified, including the right parahippocampal gyrus, right precuneus, and juxtacortical white matter (all p < 0.05). There was no correlation between fatigue scores and brain atrophy and lesion load in patients with MS.ConclusionSubstantia nigra microglial activation is linked to fatigue in MS. Microglial activation across key brain regions may represent a unifying mechanism for MSAF, and further evaluation of neuroimmunologic basis of MSAF is warranted.

OBJECTIVES: The purpose of this study was to determine phenotypes characterizing cardiac involvement in AL amyloidosis by using direct (fluorine-18-labeled florbetapir {[(18)F]florbetapir} positron emission tomography [PET]/computed tomography) and indirect (echocardiography and cardiac magnetic resonance [CMR]) imaging biomarkers of AL amyloidosis. BACKGROUND: Cardiac involvement in systemic light chain amyloidosis (AL) is the main determinant of prognosis and, therefore, guides management. The hypothesis of this study was that myocardial AL deposits and expansion of extracellular volume (ECV) could be identified before increases in N-terminal pro-B-type natriuretic peptide or wall thickness. METHODS: A total of 45 subjects were prospectively enrolled in 3 groups: 25 with active AL amyloidosis with cardiac involvement (active-CA), 10 with active AL amyloidosis without cardiac involvement by conventional criteria (active-non-CA), and 10 with AL amyloidosis with cardiac involvement in remission for at least 1 year (remission-CA). All subjects underwent echocardiography, CMR, and [(18)F]florbetapir PET/CT to evaluate cardiac amyloid burden. RESULTS: The active-CA group demonstrated the largest myocardial AL amyloid burden, quantified by [(18)F]florbetapir retention index (RI) 0.110 (interquartile range [IQR]: 0.078 to 0.139) min(−1), and the lowest cardiac function by global longitudinal strain (GLS), median GLS −1 1% (IQR: −8% to −13%). The remission-CA group had expanded extracellular volume (ECV) and [(18)F]florbetapir RI of 0.097 (IQR: 0.070 to 0.124 min(−1)), and abnormal GLS despite hematologic remission for >1 year. The active-non-CA cohort had evidence of cardiac amyloid deposition by advanced imaging metrics in 50% of the subjects; cardiac involvement was identified by late gadolinium enhancement in 20%, elevated ECV in 20%, and elevated [(18)F]florbetapir RI in 50%. CONCLUSIONS: Evidence of cardiac amyloid infiltration was found based on direct and indirect imaging biomarkers in subjects without CA by conventional criteria. The findings from [(18)F]florbetapir PET imaging provided insight into the preclinical disease process and on the basis of interpretation of expanded ECV on CMR and have important implications for future research and clinical management of AL amyloidosis. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145)

Karthik Ananthasubramaniam, E. Gordon DePuey, John J. Mahmarian, Raymond Russell III, Randall C. Thompson, and R. Glenn Wells are section lead authors.

This prospective study aimed to evaluate the clinical values of 11C–acetate positron emission tomography/computed tomography (PET/CT) in predicting histologic grades and survival in patients with cerebral glioma. Seventy-three patients with surgically confirmed cerebral gliomas (19 grade II, 21 grade III, and 33 grade IV) who underwent 11C–acetate PET/CT before surgery were included. Tumor-to-choroid plexus ratio (TCR), which was defined as the maximum standardized uptake value (SUV) of tumors to the mean SUV of choroid plexus, was compared between three World Health Organization (WHO) grade groups. Moreover, metabolic tumor volumes (MTV) were calculated. Progression-free survival (PFS) and overall survival (OS) curves were plotted using the Kaplan–Meier method, and differences in survival between groups were assessed using the log-rank test. Median TCR was 1.20 (interquartile range [IQR], 1.14 to 1.4) in grade II, 1.65 (IQR, 1.26 to 1.79) in grade III, and 2.53 (IQR, 1.93 to 3.30) in grade IV gliomas. Significant differences in TCR were seen among the three WHO grade groups (P

Funding Acknowledgements Spectrum Dynamics Background Traditional relative assessment of regional myocardial perfusion by single photon emission computed tomography (SPECT) has limited ability to identify multivessel coronary artery disease, as well as diffuse atherosclerosis and coronary microvascular dysfunction. Current gamma cameras with cadmium-zinc-telluride (CZT) detectors have higher temporal resolution and sensitivity and allow the acquisition of multi-frame images and quantification of absolute myocardial blood flow (MBF) and coronary flow reserve (CFR Purpose The aim of this study was to assess the accuracy and reproducibility of quantitative measurements of MBF and CFR obtained with a CZT SPECT system compared to PET in a cohort of patients with known or suspected coronary artery disease. Methods Accuracy was assessed in 22 patients who underwent dynamic rest/stress 99mTc-sestamibi-SPECT and 13N-ammonia PET myocardial perfusion imaging within two weeks of each other. Fourteen patients comprised the reproducibility cohort and underwent two dynamic 99mTc-sestamibi SPECT scans within two weeks. A rest/pharmacological stress single-day SPECT protocol was performed, using a 1:3 dose ratio. SPECT image reconstruction was performed using a spline-fitting method and SPECT MBF was quantified using a net retention kinetic model in commercially available software. Rest MBF and CFR were adjusted for heart-rate pressure product. Results Global MBF at rest and stress showed a good correlation between SPECT and PET (r = 0.814, p Conclusion MBF and CFR quantification is feasible using a CZT gamma camera and provides accurate and reproducible results that correlate with 13N-ammonia PET. This may be of special relevance in sites where PET is not available, enabling MBF and CFR quantification with CZT SPECT cameras. Abstract P361 Figure.

BACKGROUND. (18)F-florbetapir PET is emerging as an excellent quantitative tool to quantify cardiac light chain (AL) amyloidosis burden. The primary aim of this study was to determine interobserver reproducibility and intraobserver repeatability, defined per the recommendations of the Quantitative Imaging Biomarker Alliance technical performance group, of PET (18)F-florbetapir retention index (RI) in patients with cardiac AL amyloidosis. METHODS. The study cohort comprised 37 subjects with systemic AL amyloidosis enrolled in the prospective study: Molecular Imaging of Primary Amyloid Cardiomyopathy (clinicaltrials.gov NCT02641145). Using 10 mCi of (18)F-florbetapir, a 60-minute dynamic cardiac scan was acquired. Global and segmental left ventricular estimates of retention index (RI) of (18)F-florbetapir were calculated (Carimas 2.9 software, Turku, Finland). RI was analyzed twice, at least 24 hours apart, by two independent observers. Intraobserver repeatability and interobserver reproducibility were evaluated using Bland–Altman plots and scatter plots with fitted linear regression curves. RESULTS. All reproducibility (interobserver, r = 0.98) and repeatability (intraobserver, R=0.99 for each observer) measures of (18)F-florbetapir RI are excellent. On the Bland–Altman plots, the agreement limits for global (18)F-florbetapir RI were high and ranged for reproducibility (interobserver) from − 9.3 to + 9.4% (Fig. 1), and for repeatability (observer 1 from − 10.8 to + 10.7% and from − 9.2 to + 11.4%, for observer 2). CONCLUSIONS. The present study showed excellent interobserver reproducibility and intraobserver repeatability of (18)F-florbetapir PET retention index in patients with cardiac AL amyloidosis.

Space travel will expose people to high-energy, heavy particle radiation, and the cognitive deficits induced by this exposure are not well understood. To investigate the short-term effects of space radiation, we irradiated 4-month-old Alzheimer’s disease (AD)-like transgenic (Tg) mice and wildtype (WT) littermates with a single, whole-body dose of 10 or 50 cGy 56Fe ions (1 GeV/u) at Brookhaven National Laboratory. At ~1.5 months post irradiation, behavioural testing showed sex-, genotype-, and dose-dependent changes in locomotor activity, contextual fear conditioning, grip strength, and motor learning, mainly in Tg but not WT mice. There was little change in general health, depression, or anxiety. Two months post irradiation, microPET imaging of the stable binding of a translocator protein ligand suggested no radiation-specific change in neuroinflammation, although initial uptake was reduced in female mice independently of cerebral blood flow. Biochemical and immunohistochemical analyses revealed that radiation reduced cerebral amyloid-β levels and microglia activation in female Tg mice, modestly increased microhemorrhages in 50 cGy irradiated male WT mice, and did not affect synaptic marker levels compared to sham controls. Taken together, we show specific short-term changes in neuropathology and behaviour induced by 56Fe irradiation, possibly having implications for long-term space travel.

Purpose: One approach to preclinical single-photon emission computed tomography (SPECT) imaging that provides both high resolution and high sensitivity is based on imaging a mouse inside a collimating tube; many magnified pinhole projection images from a small target region, e.g., the heart, can be recorded simultaneously on multiple detectors with little multiplexing since each pinhole aperture’s opening angle is restricted to view mostly the target organ. However, to obtain complete data for reconstruction, it may be necessary to scan the mouse through the target region of the tube. The authors are developing a different approach based on acquisition and reconstruction of both low-resolution and high-resolution projection data acquired sequentially through many pinholes embedded in two tungsten tube sections of different diameters, a “scout” section and a high-resolution section, placed end-to-end along the axis of a triple-head clinical SPECT scanner. This paper describes the design procedures used to determine the geometric parameters of two new collimator-tube sections, as well as one approach for joint reconstruction of data acquired from both sections. Methods: The high-resolution section was designed by projecting as many pinhole views of a simulated mouse heart as possible over each detector’s camera, with no overlapping of heart projections and minimal overlapping between adjacent “hot” organ and cardiac projections. The authors then jointly optimized the geometric design of the scout section for a triple-detector camera system, as well as the number of maximum-likelihood expectation maximization (MLEM) iterations required to provide minimum mean-squared error of reconstructed voxel counts throughout a 7-cm axial range, with the constraints of fixed, 2.4-mm scout system resolution at the tube center for all apertures, limited multiplexing, and no detector motion. Simulated mouse projection data from both tube sections were then reconstructed to illustrate a simple approach for using high-resolution data to improve the whole-body scout images within a cylindrical region surrounding the heart. Results: The 2-cm-inner-radius high-resolution tube section accommodated 87 platinum–iridium pinhole inserts, each with a 0.3-mm square aperture; their radial distances from the centerline of the system ranged from 2.2 to 3.0 cm. The optimal radial distance to the closest scout pinhole and optimal number of MLEM iterations were 4.4 cm and 35 iterations, respectively, and the radial distances of the 39 scout pinholes ranged from 4.4 to 4.8 cm; aperture sizes ranged from 1.1 to 1.7 mm transaxially and 0.9–1.5 mm axially. After including data from the high-resolution section viewing the heart region into whole-body mouse reconstructions from scout data, the authors obtained high-resolution images of the heart, embedded within lower resolution images of the body, with minimal artifacts. Conclusions: The authors have optimized a dual-resolution collimator tube that provides both whole-body projections of a mouse and more targeted projections centered on the heart that can be jointly reconstructed to obtain high-resolution images of the heart embedded within lower-resolution whole-body images.

Purpose Noise levels of brain SPECT images are highest in central regions, due to preferential attenuation of photons emitted from deep structures. To address this problem, the authors have designed a novel collimator for brain SPECT imaging that yields greatly increased sensitivity near the center of the brain without loss of resolution. This hybrid collimator consisted of ultrashort cone-beam holes in the central regions and slant-holes in the periphery (USCB). We evaluated this collimator for quantitative brain imaging tasks. Methods Owing to the uniqueness of the USCB collimation, the hole pattern required substantial variations in collimator parameters. To utilize the lead-casting technique, the authors designed two supporting plates to position about 37 000 hexagonal, slightly tapered pins. The holes in the supporting plates were modeled to yield the desired focal length, hole length, and septal thickness. To determine the properties of the manufactured collimator and to compute the system matrix, the authors prepared an array of point sources that covered the entire detector area. Each point source contained 32 μCi of Tc-99m at the first scan time. The array was imaged for 5 min at each of the 64 shifted locations to yield a 2-mm sampling distance, and hole parameters were calculated. The sensitivity was also measured using a point source placed along the central ray at several distances from the collimator face. High-count projection data from a five-compartment brain phantom were acquired with the three collimators on a dual-head SPECT/CT system. The authors calculated Cramer-Rao bounds on the precision of estimates of striatal and background activity concentration. In order to assess the new collimation system to detect changes in striatal activity, the authors evaluated the precision of measuring a 5% decrease in right putamen activity. The authors also reconstructed images of projection data obtained by summing data from the individual phantom compartments. Results The sensitivity of the novel cone-beam collimator varied with distance from the detector face; it was higher than that of the fan-beam collimator by factors ranging from 2.7 to 162. Examination of the projections of the point sources revealed that only a few holes were distorted or partially blocked, indicating that the intensive manual fabrication process was very successful. Better reconstructed phantom images were obtained from the USCB+FAN collimator pair than from either LEHR or FAN collimation. For the left caudate, located near the center of the brain, the detected counts were 9.8 (8.3) times higher for UCSB compared with LEHR (FAN), averaged over 60 views. The task-specific SNR for detecting a 5% decrease in putamen uptake was 7.4 for USCB and 3.2 for LEHR. Conclusions The authors have designed and manufactured a novel collimator for brain SPECT imaging. The sensitivity is much higher than that of a fan-beam collimator. Because of differences between the manufactured collimator and its design, reconstruction of the data requires a measured system matrix. The authors have demonstrated the potential of USCB collimation for improved precision in estimating striatal uptake. The novel collimator may be useful for early detection of Parkinson's disease, and for monitoring therapy response and disease progression.

PURPOSE Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation. METHODS This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway–activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2. RESULTS Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]). CONCLUSION Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

Background: Microcalcifications in atherosclerotic plaques are destabilizing, predict adverse cardiovascular events, and are associated with increased morbidity and mortality. 18 F-fluoride positron emission tomography (PET)/computed tomography (CT) imaging has demonstrated promise as a useful clinical diagnostic tool in identifying high-risk plaques; however, there is confusion as to the underlying mechanism of signal amplification seen in PET-positive, CT-negative image regions. This study tested the hypothesis that 18 F-fluoride PET/CT can identify early microcalcifications. Methods: 18 F-fluoride signal amplification derived from microcalcifications was validated against near-infrared fluorescence molecular imaging and histology using an in vitro 3-dimensional hydrogel collagen platform, ex vivo human specimens, and a mouse model of atherosclerosis. Results: Microcalcification size correlated inversely with collagen concentration. The 18 F-fluoride ligand bound to microcalcifications formed by calcifying vascular smooth muscle cell derived extracellular vesicles in the in vitro 3-dimensional collagen system and exhibited an increasing signal with an increase in collagen concentration (0.25 mg/mL collagen −33.8×10 2 ±12.4×10 2 counts per minute; 0.5 mg/mL collagen −67.7×10 2 ±37.4×10 2 counts per minute; P =0.0014), suggesting amplification of the PET signal by smaller microcalcifications. We further incubated human atherosclerotic endarterectomy specimens with clinically relevant concentrations of 18 F-fluoride. The 18 F-fluoride ligand labeled microcalcifications in PET-positive, CT-negative regions of explanted human specimens as evidenced by 18 F-fluoride PET/CT imaging, near-infrared fluorescence, and histological analysis. Additionally, the 18 F-fluoride ligand identified micro and macrocalcifications in atherosclerotic aortas obtained from low-density lipoprotein receptor-deficient mice. Conclusions: Our results suggest that 18 F-fluoride PET signal in PET-positive, CT-negative regions of human atherosclerotic plaques is the result of developing microcalcifications, and high surface area in regions of small microcalcifications may amplify PET signal.

The Quality assurance of ultrasound clinical imaging systems is essential for maintaining their performance to the highest level and for complying with the requirements by various regulatory and accrediting agencies. Although there is no standardization yet, most of the quality assessment procedures available in literature are proposed for B‐mode and Doppler imaging. However, ultrasound imaging systems offer a variety of advanced imaging modes, besides B‐mode and Doppler, which are primarily aimed at improving image quality. This study presents computer‐based methods for evaluating image quality for the advanced imaging modes of ultrasound imaging systems: harmonic imaging, spatial compounding imaging, adaptive speckle reduction, and tissue aberration correction. The functions and parameters proposed for evaluating image quality are: grayscale mapping function, image contrast, contrast‐to‐noise ratio (CNR), and high‐contrast spatial resolution. We present our computer‐based methods for evaluating image quality of these modes with a number of probe and scanner combinations, which were employed to image targets in ultrasound phantoms. The functions and parameters here proposed in image quality performance evaluation are: grayscale mapping function, image contrast, CNR, and high‐contrast spatial resolution. We show that these quantities could be useful in developing standardized methods for evaluating the advanced ultrasound imaging modes, especially when the advanced mode resulted in subtle visual differences.

Purpose: Recently, a multipinhole collimator with inserts that have both rectangular apertures and rectangular fields of view (FOVs) has been proposed for SPECTimaging since it can tile the projection onto the detector efficiently and the FOVs in transverse and axial directions become separable. The purpose of this study is to investigate the image properties of rectangular-aperture pinholes with submillimeter apertures sizes. Methods: In this work, the authors have conducted sensitivity and FOV experiments for 18 replicates of a prototype insert fabricated in platinum/iridium (Pt/Ir) alloy with submillimeter square-apertures. A sinqθ fit to the experimental sensitivity has been performed for these inserts. For the FOV measurement, the authors have proposed a new formula to calculate the projection intensity of a flood image on the detector, taking into account the penumbra effect. By fitting this formula to the measured projection data, the authors obtained the acceptance angles. Results: The mean (standard deviation) of fitted sensitivity exponents q and effective edge lengths we were, respectively, 10.8 (1.8) and 0.38 mm (0.02 mm), which were close to the values, 7.84 and 0.396 mm, obtained from Monte Carlo calculations using the parameters of the designed inserts. For the FOV measurement, the mean (standard deviation) of the transverse and axial acceptances were 35.0° (1.2°) and 30.5° (1.6°), which are in good agreement with the designed values (34.3° and 29.9°). Conclusions: These results showed that the physical properties of the fabricated inserts with submillimeter aperture size matched our design well.

Radionuclide myocardial perfusion imaging (MPI) plays a vital role in the evaluation and management of patients with coronary artery disease. However, because of a steep growth in MPI in the mid 2000s, concerns about inappropriate use of MPI and imaging-related radiation exposure increased. In response, the professional societies developed appropriate-use criteria for MPI. Simultaneously, novel technology, image-reconstruction software for traditional scanners, and dedicated cardiac scanners emerged and facilitated the performance of MPI with low-dose and ultra-low-dose radiotracers. This paper provides a practical approach to performing low-radiation-dose MPI using traditional and novel technologies.

Purpose: Triple coincidences in positron emission tomography (PET) are events in which three γ-rays are detected simultaneously. These events, though potentially useful for enhancing the sensitivity of PET scanners, are discarded or processed without special consideration in current systems, because there is not a clear criterion for assigning them to a unique line-of-response (LOR). Methods proposed for recovering such events usually rely on the use of highly specialized detection systems, hampering general adoption, and/or are based on Compton-scatter kinematics and, consequently, are limited in accuracy by the energy resolution of standard PET detectors. In this work, the authors propose a simple and general solution for recovering triple coincidences, which does not require specialized detectors or additional energy resolution requirements. Methods: To recover triple coincidences, the authors’ method distributes such events among their possible LORs using the relative proportions of double coincidences in these LORs. The authors show analytically that this assignment scheme represents the maximum-likelihood solution for the triple-coincidence distribution problem. The PET component of a preclinical PET/CT scanner was adapted to enable the acquisition and processing of triple coincidences. Since the efficiencies for detecting double and triple events were found to be different throughout the scanner field-of-view, a normalization procedure specific for triple coincidences was also developed. The effect of including triple coincidences using their method was compared against the cases of equally weighting the triples among their possible LORs and discarding all the triple events. The authors used as figures of merit for this comparison sensitivity, noise-equivalent count (NEC) rates and image quality calculated as described in the NEMA NU-4 protocol for the assessment of preclinical PET scanners. Results: The addition of triple-coincidence events with the authors’ method increased peak NEC rates of the scanner by 26.6% and 32% for mouse- and rat-sized objects, respectively. This increase in NEC-rate performance was also reflected in the image-quality metrics. Images reconstructed using double and triple coincidences recovered using their method had better signal-to-noise ratio than those obtained using only double coincidences, while preserving spatial resolution and contrast. Distribution of triple coincidences using an equal-weighting scheme increased apparent system sensitivity but degraded image quality. The performance boost provided by the inclusion of triple coincidences using their method allowed to reduce the acquisition time of standard imaging procedures by up to ∼25%. Conclusions: Recovering triple coincidences with the proposed method can effectively increase the sensitivity of current clinical and preclinical PET systems without compromising other parameters like spatial resolution or contrast.

Although current PET scanners are designed and optimized to detect double coincidence events, there is a significant amount of triple coincidences in any PET acquisition. Triple coincidences may arise from causes such as: inter-detector scatter (IDS), random triple interactions (RT), or the detection of prompt gamma rays in coincidence with annihilation photons when non-pure positron-emitting radionuclides are used (β(+)γ events). Depending on the data acquisition settings of the PET scanner, these triple events are discarded or processed as a set of double coincidences if the energy of the three detected events is within the scanner's energy window. This latter option introduces noise in the data, as at most, only one of the possible lines-of-response defined by triple interactions corresponds to the line along which the decay occurred. Several novel works have pointed out the possibility of using triple events to increase the sensitivity of PET scanners or to expand PET imaging capabilities by allowing differentiation between radiotracers labeled with non-pure and pure positron-emitting radionuclides. In this work, we extended the Monte Carlo simulator PeneloPET to assess the proportion of triple coincidences in PET acquisitions and to evaluate their possible applications. We validated the results of the simulator against experimental data acquired with a modified version of a commercial preclinical PET/CT scanner, which was enabled to acquire and process triple-coincidence events. We used as figures of merit the energy spectra for double and triple coincidences and the triples-to-doubles ratio for different energy windows and radionuclides. After validation, the simulator was used to predict the relative quantity of triple-coincidence events in two clinical scanners assuming different acquisition settings. Good agreement between simulations and preclinical experiments was found, with differences below 10% for most of the observables considered. For clinical scanners and pure positron emitters, we found that around 10% of the processed double events come from triple coincidences, increasing this ratio substantially for non-pure emitters (around 25% for (124)I and > 50% for (86)Y). For radiotracers labeled with (18)F we found that the relative quantity of IDS events in standard acquisitions is around 18% for the preclinical scanner and between 14 and 22% for the clinical scanners. For non-pure positron emitters like (124)I, we found a β(+)γ triples-to-doubles ratio of 2.5% in the preclinical scanner and of up to 4% in the clinical scanners.

The expansion of the laser-induced bubble is the main mechanism in the developed microjet injector. In this study, Nd:YAG and Er:YAG lasers are used as triggers of the bubble formation. The impact of the laser parameters on the bubble dynamics is studied and the performance of the injector is evaluated. We found that the main cause of the differences in the bubble behavior comes from the pulse duration and wavelength. For Nd:YAG laser, the pulse duration is very short relative to the bubble lifetime making the behavior of the bubble close to that of the cavitation bubble, while in Er:YAG case, the high absorption in the water and long pulse duration change the initial behavior of the bubble making it close to a vapor bubble. The contraction and subsequent rebound are typical for cavitation bubbles in both cases. The results show that the laser-induced microjet injector generates velocity which is sufficient for the drug delivery for both laser beams of different pulse duration. We estimate the typical velocity within 30–80 m/s range and the breakup length to be larger than 1 mm suitable for trans-dermal drug injection.

A nanosecond pulse laser generates acoustic waves on a water-material interface. The absorbed beam energy heats and thermoelastically expands the material. The thermoelastic stress of a material is dependent on its absorbance and expansion coefficient. In this work, we used a composite of reduced graphene oxide (RGO) and aluminum thin film to increase the efficiency of conversion from beamed energy to thermoelastic stress. A laser shadowgraph showed enhanced acoustic waves propagating at ~1,500 m/s under water. The effect of RGO on ultrasound generation is examined for different thicknesses of RGO at several laser fluences. The pressure of laser-induced ultrasound on the RGO–aluminum composite was measured to be up to 59 times greater than that produced with an aluminum film alone, and the frequency of laser-induced ultrasound was determined by the thermoelastic response. The strong intensity and broad bandwidth of the laser-induced acoustic wave suggested enhanced repetition time and resolution required for biomedical imaging.

Ultrasound (US) has become increasingly important in imaging and image-guided interventional procedures. In order to ensure that the imaging equipment performs to the highest level achievable and thus provides reliable clinical results, a number of quality control (QC) methods have been developed. Such QC is increasingly required by accrediting agencies and professional organizations; however, these requirements typically do not include detailed procedures for how the tests should be performed. In this paper, a detailed overview of QC methods for general and breast US imaging using computer-based objective methods is described. The application of QC is then discussed within the context of a common clinical application (US-guided needle biopsy) as well as for research applications, where QC may not be mandated, and thus is rarely discussed. The implementation of these methods will help in finding early stage equipment faults and in optimizing image quality, which could lead to better detection and classification of suspicious findings in clinical applications, as well as improving the robustness of research studies.

Metal radionuclide solutions at neutral pH adhere to plastic containers. Adsorption of radionuclides on the walls of phantoms leads to a nonuniform activity distribution, which could adversely affect imaging studies, as well as phantom-based validations of absorbed dose calculations used in radioimmunotherapy, requiring accurate knowledge of the underlying activity distribution. In the work reported here, the authors determined the degree of metal chelation required to minimize metallic radionuclide oxide formation and adsorption on phantom walls in order to yield more reliable experimental data for validating image-based dosimetry. Using hollow spherical plastic phantoms, the authors evaluated three different radionuclides, I-131, In-111, and Y-90, in solutions containing three different concentrations of the chelator, ethylenediaminetetraacetate (EDTA). Adsorption to plastic walls was determined using microSPECT imaging and/or by counting aliquots of solutions. Reconstructed images and measurements of I-131 activity showed that it was uniformly distributed within all spheres; however, images of In-111 in 0.25-microM EDTA indicated that the activity concentration near the wall was much higher than that in the middle of the sphere. The decrease in activity concentration near the center of the spheres was approximately 47%. Y-90 in 0.25-microM EDTA behaved similarly; the activity concentration of Y-90 decreased by 46%. For an In-111 or Y-90 radioactivity concentration of 0.74 MBq/mL, a 2.5-microM EDTA solution was required to achieve a uniform distribution, suggesting that, under our experimental conditions, approximately 700 EDTA molecules were required for each radiometal atom to prevent precipitation and adsorption on poly(methylmethacrylate). For certain radiometals, e.g., In-111 or Y-90, adequate chelation is essential to achieve uniform activity concentration values and homogeneous distribution within the phantom compartments.

To correlate 18F-FDG uptake on PET/CT with patterns of arterial and portal perfusion on multi-detector CT (MDCT) in patients with hepatocellular carcinoma (HCC) and to assess the value of variables from PET/CT and MDCT in predicting histological grades and overall survival.We retrospectively analyzed MDCT and PET/CT of 66 patients with HCC who underwent surgical treatment. Tumor peak standard uptake value (SUV) was divided by the mean liver SUV (T/LSUV). The mean tumor Hounsfield unit (HU) to mean liver HU was calculated for arterial (T/LHU-A) and portal phases (T/LHU-P). All patients were divided into three groups: I, T/LHU-A ≤l and T/LHU-P1; II, T/LHU-A1 and T/LHU-P1; and III, T/LHU-A1 and T/LHU-P ≥1. The relationships between the CT perfusion groups and T/LSUV were assessed. Multivariate logistic regression analyses were performed using clinical and imaging parameters for predicting histological grade. Overall survival curves stratified by T/LSUV and CT perfusion groups were estimated using the Kaplan-Meier method.Statistically significant differences in T/LSUV were noted between groups I and II (2.29 [range 1.74-3.60] vs. 1.20 [range 1.07-1.58], P0.001) and groups I and III (2.29 [range 1.74-3.60] vs. 1.30 [range 1.07-1.43], P0.001). In multivariate analysis, a T/LSUV cutoff of1.46 was the only independent predictor of tumor grade, with an odds ratio of 8.462 (95% confidence interval 1.799-39.803). Kaplan-Meier curves showed significant differences in OS according to T/LSUV1.62, group I perfusion pattern, and T/LSUV1.62 plus group I perfusion pattern (P = 0.04, P = 0.021, and P = 0.002, respectively).18F-FDG PET/CT is not commonly used for detecting HCC due to its limited sensitivity. We found that increased 18F-FDG uptake is associated with decreased arterial and portal perfusion on MDCT. This can be used to preselect patients who would benefit the most from PET/CT. Meanwhile, 18F-FDG uptake remained as the only independent predictor of histological grade, and higher 18F-FDG uptake and lower perfusion pattern on MDCT were significantly related to shorter OS.

In Positron Emission Tomography, there are several causes of quantitative inaccuracy, such as partial volume or spillover effects. The impact of these effects is greater when using radionuclides that have a large positron range, e.g. (68)Ga and (124)I, which have been increasingly used in the clinic. We have implemented and evaluated a local projection algorithm (LPA), originally evaluated for SPECT, to compensate for both partial-volume and spillover effects in PET. This method is based on the use of a high-resolution CT or MR image, co-registered with a PET image, which permits a high-resolution segmentation of a few tissues within a volume of interest (VOI) centered on a region within which tissue-activity values need to be estimated. The additional boundary information is used to obtain improved activity estimates for each tissue within the VOI, by solving a simple inversion problem. We implemented this algorithm for the preclinical Argus PET/CT scanner and assessed its performance using the radionuclides (18)F, (68)Ga and (124)I. We also evaluated and compared the results obtained when it was applied during the iterative reconstruction, as well as after the reconstruction as a postprocessing procedure. In addition, we studied how LPA can help to reduce the 'spillover contamination', which causes inaccurate quantification of lesions in the immediate neighborhood of large, 'hot' sources. Quantification was significantly improved by using LPA, which provided more accurate ratios of lesion-to-background activity concentration for hot and cold regions. For (18)F, the contrast was improved from 3.0 to 4.0 in hot lesions (when the true ratio was 4.0) and from 0.16 to 0.06 in cold lesions (true ratio = 0.0), when using the LPA postprocessing. Furthermore, activity values estimated within the VOI using LPA during reconstruction were slightly more accurate than those obtained by post-processing, while also visually improving the image contrast and uniformity within the VOI.

Background— 18 F-florbetapir is a promising imaging biomarker for cardiac light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). Our aim, using human autopsy myocardial specimens, was to test the hypothesis that 18 F-florbetapir binds specifically to myocardial AL and ATTR amyloid deposits. Methods and Results— We studied myocardial sections from 30 subjects with autopsy-documented AL (n=10), ATTR (n=10), and nonamyloid controls (n=10) using 18 F-florbetapir and cold florbetapir compound and digital autoradiography. Total and nonspecific binding of 18 F-florbetapir was determined using the maximum signal intensity values. Specific binding of 18 F-florbetapir was calculated by subtracting nonspecific from total binding measurements (in decays per minute/mm 2 , DPM mm 2 ) and was compared with cardiac structure and function on echocardiography and the histological extent of amyloid deposits. Diffuse or focally increased 18 F-florbetapir uptake was noted in all AL and ATTR samples and in none of the control samples. Compared with control samples, mean 18 F-florbetapir–specific uptake was significantly higher in the amyloid samples (0.94±0.43 versus 2.00±0.58 DPM/mm 2 ; P 2 ; P 18 F-florbetapir–specific uptake compared with control samples (1.50±0.17 versus 0.94±0.43 DPM/mm 2 ; P =0.004), despite smaller amyloid extent than in subjects with typical echocardiograms. Conclusions— 18 F-florbetapir specifically binds to myocardial AL and ATTR deposits in humans and offers the potential to screen for the 2 most common types of myocardial amyloid.

We have incorporated Monte Carlo (MC)-based estimates of patient scatter, detector scatter, and crosstalk into an iterative reconstruction algorithm, and compared its performance to that of a general spectral (GS) approach. We extended the MC-based reconstruction algorithm of de Jong et al. by (1) using the “Delta scattering” method to determine photon interaction points, (2) simulating scatter maps for many energy bins simultaneously, and (3) decoupling the simulation of the object and detector by using pre-stored point spread functions (PSF) that included all collimator and detector effects. A numerical phantom was derived from a segmented CT scan of a torso phantom. The relative values of In-111 activity concentration simulated in soft tissue, liver, spine, left lung, right lung, and five spherical tumors (1.3–2.0 cm diam.) were 1.0, 1.5, 1.5, 0.3, 0.5, and 10.0, respectively. GS scatter projections were incorporated additively in an OSEM reconstruction (6 subsets×10 projections×2 photopeak windows). After three iterations, GS scatter projections were replaced by MC-estimated scatter projections for two additional iterations. MC-based compensation was quantitatively compared to GS-based compensation after five iterations. The bias of organ activity estimates ranged from −13% to −6.5% (GS), and from −1.4% to +5.0% (MC); tumor bias ranged from −20.0% to +10.0% for GS (mean±std.dev.=−4.3±11.9%), and from −2.2 to +18.8% for MC (+4.1±8.6%). Image noise in all organs was less with MC than with GS.

New collimator manufacturing technologies, such as photoetching, electrical discharge machining, and stereolithography, expand the range of possible cone-beam collimator configurations. For example, it might now be possible for brain SPECT to make a short-focusing cone-beam collimator with tapered holes that increase in size with distance from the collimator surface; conventional lead-casting techniques produce holes of constant size and, consequently, varying septal thicknesses. Moreover, the changes in hole shape and loss of close packing due to focusing leads to thicker septa in the collimator periphery, especially for shorter focal lengths. We investigated the potential advantages of new cone-beam collimator manufacturing processes, and proposed a new design for very short focal-length collimators for brain SPECT imaging. We compared three cone-beam collimators, a conventional collimator manufactured using casting techniques (CC), a novel collimator with uniform hole sizes on the collimator surface and constant hole size through the collimator thickness (FC), and a novel collimator with uniform hole sizes and tapered holes (TC). We determined the resolution of each collimator analytically for focal lengths ranging from 20–50 cm, and adjusted the entrance hole sizes of FC and TC to equalize resolution of all collimators. Sensitivity was calculated at several locations by Monte Carlo simulation. Sensitivity was higher at all points for TC and FC than for CC, and higher for TC than for FC. The differences in sensitivity were larger for shorter focal lengths. For a point on the focal line at 10 cm in front of the collimator entrance surface, the sensitivity gain for TC compared to CC was 7% and 45% for focal lengths of 50 and 20 cm, respectively. The sensitivity gain for a 20-cm focal length, compared to CC, averaged over all locations, was 44% for TC and 23% for FC. We have shown that the new collimator designs made possible by new manufacturing techniques will provide gains in sensitivity that depend strongly on focal length; the sensitivity gains are large for the very short focal lengths that, as we have previously shown, are beneficial for brain imaging.

Single-photon emission-computed tomography (SPECT) imaging of deep brain structures is compromised by loss of photons due to attenuation. We have previously shown that a centrally peaked collimator sensitivity function can compensate for this phenomenon, increasing sensitivity over most of the brain. For dual-head instruments, parallel-hole collimators cannot provide variable sensitivity without simultaneously degrading spatial resolution near the center of the brain; this suggests the use of converging collimators. We have designed collimator pairs for dual-head SPECT systems to increase sensitivity, particularly in the center of the brain, and compared the new collimation approach to existing approaches on the basis of performance in estimating activity concentration of small structures at various locations in the brain. The collimator pairs we evaluated included a cone-beam collimator, for increased sensitivity, and a fan-beam collimator, for data sufficiency. We calculated projections of an ellipsoidal uniform background, with 0.9-cm-radius spherical lesions at several locations in the background. From these, we determined ideal signal-to-noise ratios (SNRCRB) for estimation of activity concentration within the spheres, based on the Cramer-Rao lower bound on variance. We also reconstructed, by an ordered-subset expectation-maximization (OS-EM) procedure, images of this phantom, as well as of the Zubal brain phantom, to allow visual assessment and to ensure that they were free of artifacts. The best of the collimator pairs evaluated comprised a cone-beam collimator with 20 cm focal length, for which the focal point is inside the brain, and a fan-beam collimator with 40 cm focal length. This pair yielded increased SNRCRB, compared to the parallel-parallel pair, throughout the imaging volume. The factor by which SNRCRB increased ranged from 1.1 at the most axially extreme location to 3.5 at the center. The gains in SNRCRB were relatively robust to mismatches between the center of the brain and the center of the imaging volume. Artifact-free reconstructions of simulated data acquired using this pair were obtained. Combining fan-beam and short-focusing cone-beam collimation should greatly improve dual-head brain SPECT imaging, especially for centrally located structures.

Purpose: Two separate low-dose CT scans are usually performed for attenuation correction of rest and stress N-13 ammonia PET/CT myocardial perfusion imaging (PET/CT). We utilize an automatic exposure control (AEC) technique to reduce CT radiation dose while maintaining perfusion image quality. Our goal is to assess the reproducibility of displayed CT dose index (CTDI) on same-day repeat CT scans (CT1 and CT2). Methods: Retrospectively, we reviewed CT images of PET/CT studies performed on the same day. Low-dose CT utilized AEC technique based on tube current modulation called Smart-mA. The scan parameters were 64 × 0.625mm collimation, 5mm slice thickness, 0.984 pitch, 1-sec rotation time, 120 kVp, and noise index 50 with a range of 10–200 mA. The scan length matched with PET field of view (FOV) with the heart near the middle of axial FOV. We identified the reference slice number (RS) for an anatomical landmark (carina) and used it to estimate axial shift between two CTs. For patient size, we measured an effective diameter on the reference slice. The effect of patient positioning to CTDI was evaluated using the table height. We calculated the absolute percent difference of the CTDI (%diff) for estimation of the reproducibility. Results: The study included 168 adults with an average body-mass index of 31.72 ± 9.10 (kg/m2) and effective diameter was 32.72 ± 4.60 cm. The average CTDI was 1.95 ± 1.40 mGy for CT1 and 1.97 ± 1.42mGy for CT2. The mean %diff was 7.8 ± 6.8%. Linear regression analysis showed a significant correlation between the table height and %diff CTDI. (r=0.82, p

Pyroglutamate-3 Av (pGlu-3 Av) is a highly pathogenic Av species in Alzheimer's disease (AD) brain. The Av N-terminus is truncated and the 3rd residue (glu) cyclized by glutaminyl cyclase, leading to increased aggregation and neurotoxicity. Previously, we reported that chronic treatment in young AD transgenic (Tg) mice with 07/1, an anti-pGlu-3 Av IgG1 mAb, staved off AD-like changes (Frost et al., 2012, 2015). Here, we compared different Ig isotypes of an anti-pGlu-3 Av mAb using ex vivo phagocytosis, longitudinal microglial PET imaging with TSPO-specific 18F-GE180, and therapeutic passive immunotherapy (IT) in plaque-bearing, aged APP/PS1dE9 Tg mice. 07/2a, an IgG2a version of the 07 mAb, was more effective than the 07/1 mAb at microglia-mediated Av clearance in mouse brain by ex vivo phagocytosis. Next, 4 and 16 mo Tg mice underwent baseline 18F-GE180 PET scans on Day 0, followed by a single i.p. injection of 500 mg of 07/1, 07/2a, or 3A1 (a pan-Av IgG1 mAb), or PBS. Hippocampal uptake of 18F-GE180 was increased in 07/2a-treated mice at Days 3 and 30 in 4 mo Tg mice and was increased at Day 3 but reduced at Day 30 in 16 mo Tg mice; 07/1-treatment resulted in increased 18F-GE180 uptake only at Day 30 at both ages, while 3A1-treatment resulted in reduced uptake at Days 3 and 30 at both ages. Therapeutic IT was performed in 12 mo-old male Tg mice (n = 15/group) given weekly i.p. injections with 300 mg of 07/1, 07/2a, or 3A1, or PBS, for 16 wk. Mice underwent Open Field (OF), Water T Maze (WTM) and Context Fear Conditioning (CFC) testing at 15 mo and sacrifice at 16 mo. Mice treated with 07/2a showed significant benefit in spatial learning and memory in acquisition (p < 0.05) and reversal (cognitive flexibility; p < 0.05) WTM compared to Tg-PBS mice. CFC and microhemorrhages were similar between groups. 07/2a-treated mice had significantly less pGlu-3 Av immunoreactivity (p < 0.01), and 07/1-treated mice showed a trend for a reduction, vs. PBS-treated mice. Thus, selective targeting of pGlu-3 Av aggregates with an IgG2a mAb is effective in lowering plaque burden in the absence of microhemorrhage, while improving cognitive performance in aged APP/PS1dE9 Tg mice.

Our study aimed to examine the relationship between perceived sleep quality and depression using Pittsburgh Sleep Quality Index (PSQI) and Cole's model to materialize the concept of perceived sleep quality in the non-cognitively impaired elderly. Older adults aged 60+ were recruited from the baseline study of Suwon Project (SP) between 2009 and 2011 (n=2040). Perceived sleep quality was measured using the Korean version of the Pittsburgh Sleep Quality Index (PSQI-K), and depression was accessed using the Korean version of the Geriatric Depression Scale-Short Form (SGDS-K). We excluded the cognitively impaired elderly using the Korean version-Mini Mental Status Examination (K-MMSE) score less than or equal to 17. In multivariable adjusted logistic regression related to PSQI-K components, poor perceived sleep quality, including poor subjective sleep quality (Odds ratio (OR)=1.27, 95% confidence interval (CI)=1.01-1.61), longer sleep latency (OR=1.32, 95% CI=1.13-1.55) and the frequent use of sleeping medication (OR=1.30, 95% CI=1.10-1.53) were significantly associated with depression after adjusting for age, sex, education, living status, current smoking and current alcohol drinking, the number of comorbidity and Beck Anxiety Inventory (BAI). PSQI-K global score also had greater odds of reporting depression (OR=1.12, 95% CI=1.07-1.16). These results suggested that poor perceived sleep quality was associated with a greater level of depression in the elderly.

MicroSPECT systems providing high resolution and high sensitivity are often based on imaging a mouse inside a tube with many pinholes. Projection images from a small target region, e.g., heart or brain, can be recorded simultaneously on multiple detectors with little multiplexing since each pinhole aperture can be restricted to view just the target region; however, this often requires that much of the mouse body be scanned through the target region of the collimating tube to obtain complete data for reconstruction. We describe another approach for joint reconstruction of both low- and high-resolution projection data acquired sequentially through many rectangular pinholes embedded in two tungsten tube sections of different diameter, placed end-to-end along the axis of a 3-head clinical SPECT scanner. One section provides a whole-body scout image of good sensitivity, but limited resolution, for locating the primary organ of interest and acquiring complete data for reconstruction. A second, 'hi-res' section, which contains many smaller pinholes, is then moved into place axially over the mouse, which is also moved to position its target organ in the center of the gantry. We optimized a scout section for a Trionix triple-head SPECT system to provide minimum mean-squared error of reconstructed voxel counts throughout a ∼6-cm axial range, with the constraints of fixed 2.4-mm scout system resolution, limited multiplexing, and no detector motion. The optimal radial distance to the closest scout pinhole and optimal number of MLEM iterations were 4.4 cm and 60 iterations, respectively; radial distances of the 30 pinholes ranged from 4.4 to 4.8 cm. After including whole-body mouse reconstructions of simulated 30-pinhole scout data into reconstructions of data from 93, 0.33-mm pinholes in a hi-res section viewing the heart region, we obtained high-resolution images of the heart, embedded in lower resolution images of the body, with minimal artifacts.

Recently, a square-pinhole collimator has been proposed for SPECT imaging since it can tile the projection onto the detector efficiently and the fields of view (FOVs) in transverse and axial directions become separable. In this work, we have conducted sensitivity and FOV experiments for eighteen fabricated platinum/iridium(Pt/Ir) inserts with sub-millimeter square-apertures. A sinqθ fit to the experimental sensitivity has been performed for these inserts. The mean (standard deviation) of fitted sensitivity exponents (q) and effective diameters (d) are 10.7 (1.3) and 0.35 mm (0.02 mm), which are close to the values obtained from the simulated sensitivity data generated using the geometric parameters of the designed inserts. From projections of the FOV on the detector, we have measured the acceptance angles in the transverse and axial directions. The measured mean (standard deviation) of transverse and axial half-acceptances are 17.33° (0.21°) and 15.03°(0.23°), which are in good agreement with the designed values (17.13° and 14.93°). These results show that the physical properties of the fabricated inserts with sub-millimeter aperture size match our design well.

We present a new approach to decision making based on the concept of emission counts (EC), i.e., the number of events emitted per voxel during the scan. The approach allows direct computation of posterior probabilities of hypotheses defined in terms of EC, and is applicable to any type of emission tomographic list-mode projection data, e.g., SPECT, PET, or time-of-flight (TOF)-PET, as well as binned data which can be considered a special case of list-mode data. Conditional Bayesian (CB) decision theory utilizing values of the posterior probability of hypotheses as test statistics are used to derive decision rules. We demonstrate that the derived decision principle is equivalent to the likelihood-ratio ideal observer for binary hypothesis testing. We use data acquired in list-mode format for an anthropomorphic torso phantom using a lanthanum-bromide time-of-flight PET scanner to provide examples of application of EC-CB observer. For data-specific decisions, we demonstrate examples of multiple-hypotheses decision making. For imaging system evaluation, we define two regions of interest (ROls) on the image, and two hypotheses, H1 and H2, that one ROI emitted on average at least r times more events than the other region. The posterior probabilities of H1 and H2 are determined. ROC curves are constructed using 50 projection data sets (list-mode tiles), each including 16 million prompts, from which 25 data sets correspond to H1 and the other 25 to H2. The areas and partial areas under the ROC curves are used as figures of merit evaluating the performance of the LaBr3 PET system in discriminating between H1 and H2 with and without TOF information. Summary: A new optimal numerical observer which makes decisions based on posterior probability of emission counts is presented. The utility of the observer for hypothesis testing is demonstrated on TOF list-mode phantom data acquired on PENN LaPET scanner.

We have studied the impact of using rectangular-aperture pinholes in a multi-pinhole, stationary system for cardiac imaging of mice. The system will utilize the standard NaI(TI) detectors on a clinical SPECT system. There are at least two advantages to using rectangular apertures: (1) the fields of view (FOV) in the axial and transverse directions become separable since they are determined by the walls of the aperture insert, which can have independent acceptance angles; and (2) the tiling of projections onto the detector is more efficient for the same solid angle (i.e., allows more pinholes) than traditional, circular apertures since the circular-aperture projections have a packing fraction of less than π/4. The system design places these rectangular apertures, which will be cast using a Pt/Ir alloy that is denser and harder than gold, into a tungsten-polymer tube that will be cast from a mold that is 3D printed in plastic. This fabrication technique will provide flexibility in the placement and orientation of the pinhole inserts yet will be less expensive to manufacture than traditional machining. The system sensitivity depends on the resolution and FOV; we plan to limit the FOV to a region that accommodates a mouse heart with some margin. We have tested the reconstruction of simulated data, with both point phantoms and the MOBY™ phantom, using an MLEM algorithm and found both good resolution and fidelity throughout the targeted FOV, with good angular sampling. The system can achieve an estimated best system resolution of 0.4 mm with high magnification - before resolution recovery by system modeling during reconstruction - but this operating point would yield low sensitivity. Comparisons with commercial and research systems indicate improved sensitivity at the same resolution.

Intra-arterial administration of Y-90-microspheres is an established technique for radioembolization of hepatic tumors. We have previously developed a new approach for rapid simulation of bremsstrahlung from Y -90 beta particles; this method is being incorporated into the forward projector of a Monte Carlo (MC)-based SPECT reconstruction program. Conditional probability densities, derived from EGSnrc simulations, were first used to obtain multi-dimensional tables of equally likely parameters for bremsstrahlung production. Rapid simulation then consisted of randomly selecting a beta energy from a table of 100 equiprobable energies, a radial distance to the location of bremsstrahlung production for the given beta energy, and an equiprobable photon energy for the given beta energy and range. The rare nuclear de-excitation and internal pair-production processes yielding 1760- and 511-keV photons were also included. Simulated photons were used to build tables of distance- and energy-dependent resolution kernels (PSFs), including all collimator and detector interactions, and were also propagated through an attenuation map for 8 orders of scatter, yielding scatter-map (S-map) images in 40 energy bins from 59 to 859 keV. Primary and S-map photons were projected into 6 detector energy windows from 59 to 563 keV using convolution-forced detection (CFD) with the precomputed PSFs. Data were simulated and acquired from a 2.5-cm-diameter sphere of Y -90 centered within a water cylinder (7.2-cm diam. × 10.3 cm long). Energy spectra and projection images in the 6 windows were recorded with this phantom positioned ~20 cm from the high-energy general-purpose collimators on a Siemens Symbia SPECT-CT scanner. Acquired and simulated spectra and images were in good agreement. The average absolute difference of counts between fully-MC-simulated and Smap+CFD-computed images was 13.6%; discrepancies can be further reduced by using wider CFD kernels for the highest energy windows.

We have developed a neσw method of compensating for effects of partial volume and spillover in dual-modality imaging. The approach requires segmentation of just a few tissue types within a small volume-of-interest (VOI) surrounding a lesion; the algorithm estimates simultaneously, from projection data, the activity concentration within each segmented tissue inside the VOI. Measured emission projections were fitted to the sum of resolution-blurred projections of each such tissue, scaled by its unknown activity concentration, plus a global background contribution obtained by reprojection through the reconstructed image volume outside the VOI. The method was evaluated using multiple-pinhole μSPECT data simulated for the MOBY mouse phantom containing two spherical lung tumors and one liver tumor, as well as using multiple-bead phantom data acquired on μSPECT and μCT scanners. Each VOI in the simulation study was 4.8 mm (12 voxels) cubed and, depending on location, contained up to four tissues (tumor, liver, heart, lung) with different values of relative 99mTc concentration. All tumor activity estimates achieved

Purpose: Large axial field-of-view (FOV) PET/CT scanners are valued for high sensitivity. Brain PET image quality may depend on the head position within the FOV. We investigated the precision of activity estimation for brain PET imaging when the brain was positioned at the end (END) and in the middle (CEN) of the FOV. The additional CT dose for the CEN position was recorded. Methods: An image quality (Jaszczak) phantom and a striatal phantom were filled with F-18 and positioned in END and CEN locations. For each phantom and each location, we acquired a ∼1-hr listmode PET, rebinned the data into 10 frames with equal number of coincidence events, and reconstructed each frame using an iterative algorithm. For the striatal phantom, END and CEN were compared by drawing on each image three regions of interest (ROI) in axially separated uniform areas. The standard deviation of the activity estimation within each ROI was averaged over the 10 images. The coefficient of variation (CV) for activity estimation was calculated at each position. Image quality was assessed by inspecting the resolution bar pattern in the Jaszczak phantom at two different head positions. Results: The CV was the lowest for ROIs near the center ofmore » the FOV. For slices near the end, not only was the CV highest, but also the resolution pattern was degraded. CTDIvol summarized in the dose report indicated that the CT dose was ∼ 10% higher for CEN as compared to END position. Conclusion: Positioning the brain in the middle of the FOV in a large FOV PET/CT scanner allows more precise measurement of tracer uptake and better image quality at the cost of increased CT dose. For the end location longer scan times may minimize image quality degradation without any additional CT dose.« less

Objective— Reduced limb perfusion from arterial stenosis does not adequately account for intermittent claudication symptoms in peripheral artery disease (PAD). Insulin resistance is associated with PAD and may contribute to claudication by impairing skeletal muscle metabolism. We aimed to determine whether skeletal muscle glucose uptake, assessed by [ 18 F]fluorodeoxyglucose positron emission tomography, is reduced in patients with claudication. Methods and Results— Thirty-seven subjects with PAD and claudication and 11 healthy controls underwent [ 18 F]fluorodeoxyglucose–positron emission tomography imaging of the legs during hyperinsulinemic-euglycemic clamp. Calf glucose uptake was quantified by graphical Patlak analysis, and whole-body insulin sensitivity was assessed as the glucose disposal rate (M) from the insulin clamp. Compared with healthy controls, PAD subjects were insulin resistant (M=3.4 mg/kg per minute [interquartile range, 2.7 to 4.8] versus 5.0 [3.7 to 6.6], P =0.019). Calf muscle glucose uptake was significantly lower in PAD compared with healthy subjects (48.6±2.6 μmol/kg per minute versus 62.9±6.5 μmol/kg per minute, P =0.009) and correlated with systemic insulin sensitivity ( r =0.37, P =0.03) in PAD subjects. These abnormalities persisted even after exclusion of PAD subjects with diabetes. Conclusion— Patients with claudication have impaired calf muscle glucose uptake. Future studies are required to assess whether calf muscle insulin resistance contributes to exercise limitation in patients with intermittent claudication.

Increasing the number of pinholes in small-animal SPECT significantly improves its count sensitivity. When the detector(s) are small, however, overlapping of projections (multiplexing) from different pinholes is unavoidable and can amplify noise in reconstructed images. We have evaluated the performance of two multi-pinhole systems, one with and one without multiplexing, for a prototypical tumor-imaging task. We prepared seven beads (∼1.8-mm diameter) to mimic tumors labeled with Tc-99m. A uniform gelatin phantom was used to simulate normal background tissue. The tumor-to-normal tissue ratio was ∼6:1, and each bead contained ∼1 μCi. The first scanner, equipped with two 0.8-mm pinholes on each of three heads (HMS-0.8), acquired only non-overlapping projections. We also scanned the phantom using 1.6mm pinholes (HMS-1.6) The second scanner had 9 pinholes on each of four heads, and allowed multiplexing. To compensate for decay, the phantom was scanned for 50 min on HMS-0.8, 58 min on HMS-1.6, 82 min on NanoSPECT/CT with 1.4 mm pinholes (Nano-1.4), and 102 min with 1.0 mm pinholes (Nano-1.0). A total of 30 (24) angular projections were acquired with HMS (Nano); these were reconstructed using 10 OSEM subsets for HMS, and 4 subsets for Nano. The mean voxel value in each sphere, and the mean and standard deviation in a large VOI in the background, were used to compute the signal-to-noise ratio (SNR) and contrast of each bead. The relative noise in the background was also calculated. The systems with and without multiplexing yielded similar image quality and average bead SNR, especially for HMS-0.8 and Nano-1.0. Both systems yielded very similar SNR values, despite the fact that the multiplexed system acquired data using 36 pinholes, while the non-multiplexed system had only 6 pinholes. The multiplexed acquisition did not seem to adversely affect the image contrast of the spherical tumors.