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Anaplastic thyroid cancer is a rare but devastating malignancy. Anaplastic thyroid cancer cells exhibit the Warburg effect by preferentially undergoing glycolysis even in aerobic conditions, leading to high glucose use. Here we assess if targeted inhibition of glycolysis can diminish anaplastic thyroid cancer growth and improve outcomes.Human anaplastic thyroid cancer cell line 8505C was grown in medium containing high (25 mmol/L) or low (3 mmol/L) glucose concentration and hexokinase II inhibitor 3-bromopyruvate (200 μM). Cellular proliferation, migration, and invasion were measured. An orthotopic xenograft model of anaplastic thyroid cancer was generated in nude mice using 8505C cells. Animals were provided standard chow or a ketogenic diet and treated with 3-bromopyruvate (1.8 mg/kg). Overall survival time was monitored. Necropsies were performed to harvest tumors for analysis.Growth of 8505C in low-glucose medium with 3-bromopyruvate decreased cell proliferation by 89%, migration by 44%, and invasion by 73% (P.001 for all) compared with high glucose. Animals concomitantly receiving a ketogenic diet and 3-bromopyruvate exhibited smaller tumor volumes (P = .03), slower tumor growth rates (P = .01), and improved overall survival (P = .006) compared with standard-diet control subjects. Monotherapy with a ketogenic diet or 3-bromopyruvate alone did not reduce tumor size or increase survival over the standard-diet control group.Glycolytic inhibition with 3-bromopyruvate inhibits tumor growth and extends survival in a murine model of anaplastic thyroid cancer when combined with the ketogenic diet. Thus, targeted glycolytic inhibition of anaplastic thyroid cancer exhibits context-specific utility and may only be effective during ketosis induced by dietary restriction of glycolytic inputs.

Background: Single photon emission computed tomography (SPECT) has limited ability to identify multivessel and microvascular coronary artery disease. Gamma cameras with cadmium zinc telluride detectors allow the quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR). However, evidence of its accuracy is limited, and of its reproducibility is lacking. We aimed to validate 99m Tc-sestamibi SPECT MBF and MFR using standard and spline-fitted reconstruction algorithms compared with 13 N-ammonia positron emission tomography in a cohort of patients with known or suspected coronary artery disease and to evaluate the reproducibility of this technique. Methods: Accuracy was assessed in 34 participants who underwent dynamic 99m Tc-sestamibi SPECT and 13 N-ammonia positron emission tomography and reproducibility in 14 participants who underwent 2 99m Tc-sestamibi SPECT studies, all within 2 weeks. A rest/pharmacological stress single-day SPECT protocol was performed. SPECT images were reconstructed using a standard ordered subset expectation maximization (OSEM) algorithm with (N=21) and without (N=30) application of spline fitting. SPECT MBF was quantified using a net retention kinetic model‚ and MFR was derived as the stress/rest MBF ratio. Results: SPECT global MBF with splines showed good correlation with 13 N-ammonia positron emission tomography (r=0.81, P P P P =0.07, for MBF and MFR, respectively). Reproducibility of global MBF estimates with splines in paired SPECT scans was good (r=0.77, P P P =0.3). There were no significant differences in MBF or MFR between the 2 reproducibility scans independently of the reconstruction algorithm ( P >0.05 for all). Conclusions: MBF and MFR quantification using 99m Tc-sestamibi cadmium zinc telluride SPECT with spatiotemporal spline fitting improved the correlation with 13 N-ammonia positron emission tomography flow estimates and test/retest reproducibility. The use of splines may represent an important step toward the standardization of SPECT flow estimation.

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.

OBJECTIVES: The goals of this study were to characterize myocardial composition during the active and remission phases of light-chain (AL) cardiac amyloidosis. BACKGROUND: Cardiac dysfunction in AL amyloidosis is characterized by dual insults to the myocardium from infiltration and toxicity from light chains during the active phase and by infiltration alone in the remission phase. METHODS: Prospectively enrolled subjects with cardiac AL amyloidosis (21 remission AL amyloidosis; age: 63.4 ± 7.3 years; 47.6% male; and 48 active AL amyloidosis; age: 62.5 ± 7.4 years; 60.4% male) underwent contrast-enhanced cardiac magnetic resonance with T(1) and T(2) mapping and measurement of extracellular volume (ECV). By definition, serum free light-chain levels were normal for at least 1 year following successful AL therapy in the remission group and abnormal in the active group. RESULTS: Myocardial ECV was similarly expanded in the remission and active AL amyloidosis groups (0.488 ± 0.082 vs 0.519 ± 0.083, respectively; P = 0.15). However, myocardial T(2) relaxation times (47.7 ± 3.2 ms vs 45.5 ± 3.0 ms; P = 0.008) as well as native T(1) times (1,368 ms [IQR: 1,290–1,422 ms] vs 1,264 ms [IQR: 1,203–1,380 ms]; P = 0.024) were significantly higher in the remission compared to the active AL amyloidosis group. CONCLUSIONS: Myocardial ECV is substantially expanded in the active AL and remission AL cardiac amyloidosis groups, but native T(1) values were higher, suggesting a different myocardial composition. There is no evidence of myocardial edema in active AL cardiac amyloidosis. Future phenotyping studies of AL cardiac amyloidosis need to consider complementary myocardial markers that define the interstitial milieu in addition to changes in extracellular volume. (Molecular Imaging of Primary Amyloid Cardiomyopathy; NCT02641145)

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.

We previously described a novel “chemogenetic” animal model of heart failure that recapitulates a characteristic feature commonly found in human heart failure: chronic oxidative stress. This heart failure model uses a chemogenetic approach to activate a recombinant yeast d-amino acid oxidase in rat hearts in vivo to generate oxidative stress, which then rapidly leads to the development of a dilated cardiomyopathy. Here we apply this new model to drug testing by studying its response to treatment with the angiotensin II (ANG II) receptor blocker valsartan, administered either alone or with the neprilysin inhibitor sacubitril. Echocardiographic and [18F]fluorodeoxyglucose positron emission tomographic imaging revealed that valsartan in the presence or absence of sacubitril reverses the anatomical and metabolic remodeling induced by chronic oxidative stress. Markers of oxidative stress, mitochondrial function, and apoptosis, as well as classical heart failure biomarkers, also normalized following drug treatments despite the persistence of cardiac fibrosis. These findings provide evidence that chemogenetic heart failure is rapidly reversible by drug treatment, setting the stage for the study of novel heart failure therapeutics in this model. The ability of ANG II blockade and neprilysin inhibition to reverse heart failure induced by chronic oxidative stress identifies a central role for cardiac myocyte angiotensin receptors in the pathobiology of cardiac dysfunction caused by oxidative stress. NEW & NOTEWORTHY The chemogenetic approach allows us to distinguish cardiac myocyte-specific pathology from the pleiotropic changes that are characteristic of other “interventional” animal models of heart failure. These features of the chemogenetic heart failure model facilitate the analysis of drug effects on the progression and regression of ventricular remodeling, fibrosis, and dysfunctional signal transduction. Chemogenetic approaches will be highly informative in the study of the roles of redox stress in heart failure providing an opportunity for the identification of novel therapeutic targets.

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.

Immunoglobulin light-chain (AL) amyloidosis affects multiple systemic organs. However, determination of the precise extent of organ involvement remains challenging. Targeted amyloid imaging with 18F-florbetapir PET/CT offers the potential to detect AL deposits in multiple organs. The primary aim of this study was to determine the distribution and frequency of AL deposits in the various organs of subjects with systemic AL amyloidosis using 18F-florbetapir PET/CT. Methods: This prospective study included 40 subjects with biopsy-proven AL amyloidosis including active AL amyloidosis (n = 30) or AL amyloidosis in hematologic remission for more than 1 y (n = 10). All subjects underwent 18F-florbetapir PET/CT, skull base to below the kidney scan field, from 60 to 90 min after injection of radiotracer. Volume-of-interest measurements of SUVmax were obtained using Hermes software for the parotid gland, tongue, thyroid, lung, gastric wall, pancreas, spleen, kidney, muscle, abdominal fat, lower thoracic spine, vertebral body, and humeral head. Uptake in each organ was visually compared with that in spine bone marrow. An SUVmax of at least 2.5 was considered abnormal in all organs other than the liver. Results: Compared with the international consensus definition of organ involvement, 18F-florbetapir PET/CT identified amyloid deposits in substantially higher percentages of subjects for several organ systems, including parotid gland (50% vs. 3%), tongue (53% vs. 10%), and lung (35% vs. 10%). In several organ systems, including kidney (13% vs. 28%) and abdominal wall fat (10% vs. 13%), PET identified involvement in fewer subjects than did international consensus. Quantitative analysis of 18F-florbetapir PET/CT revealed more frequent organ involvement than did visual analysis in the tongue, thyroid, lung, pancreas, kidney, muscle, and humeral head. Extensive organ amyloid deposits were observed in active AL as well as in AL remission cohorts, and in both cardiac and noncardiac AL cohorts. Conclusion:18F-florbetapir PET/CT detected widespread organ amyloid deposition in subjects with both active AL and AL hematologic remission. In most instances, amyloid deposits in the various organs were not associated with clinical symptoms and, thus, were unrecognized. Early recognition of systemic organ involvement may help tailor treatment, and noninvasive monitoring of organ-level disease may guide management with novel fibril-resorbing therapies.

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)

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.

Breathing motion can displace internal organs by up to several cm; as such, it is a primary factor limiting image quality in medical imaging. Motion can also complicate matters when trying to fuse images from different modalities, acquired at different locations and/or on different days. Currently available devices for monitoring breathing motion often do so indirectly, by detecting changes in the outline of the torso rather than the internal motion itself, and these devices are often fixed to floors, ceilings or walls, and thus cannot accompany patients from one location to another. We have developed small ultrasound-based sensors, referred to as ‘organ configuration motion’ (OCM) sensors, that attach to the skin and provide rich motion-sensitive information. In the present work we tested the ability of OCM sensors to enable respiratory gating during in vivo PET imaging. A motion phantom involving an FDG solution was assembled, and two cancer patients scheduled for a clinical PET/CT exam were recruited for this study. OCM signals were used to help reconstruct phantom and in vivo data into time series of motion-resolved images. As expected, the motion-resolved images captured the underlying motion. In Patient #1, a single large lesion proved to be mostly stationary through the breathing cycle. However, in Patient #2, several small lesions were mobile during breathing, and our proposed new approach captured their breathing-related displacements. In summary, a relatively inexpensive hardware solution was developed here for respiration monitoring. Because the proposed sensors attach to the skin, as opposed to walls or ceilings, they can accompany patients from one procedure to the next, potentially allowing data gathered in different places and at different times to be combined and compared in ways that account for breathing motion.

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.

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.

Glioblastoma (GBM) is the most common and deadliest form of brain tumor and remains amongst the most difficult cancers to treat. Brevican (Bcan), a central nervous system (CNS)-specific extracellular matrix protein, is upregulated in high-grade glioma cells, including GBM. A Bcan isoform lacking most glycosylation, dg-Bcan, is found only in GBM tissues. Here, dg-Bcan is explored as a molecular target for GBM. In this study, a d-peptide library is screened to identify a small 8-amino acid dg-Bcan-Targeting Peptide (BTP) candidate, called BTP-7 that binds dg-Bcan with high affinity and specificity. BTP-7 is preferentially internalized by dg-Bcan-expressing patient-derived GBM cells. To demonstrate GBM targeting, BTP-7 is radiolabeled with 18F, a radioisotope of fluorine, and increased radiotracer accumulation is found in intracranial GBM established in mice using positron emission tomography (PET) imaging. dg-Bcan is an attractive molecular target for GBM, and BTP-7 represents a promising lead candidate for further development into novel imaging agents and targeted therapeutics.

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.

Cardiac amyloidosis, once considered untreatable, is now gaining well-deserved attention due to advances in imaging and the recent approval of targeted breakthrough therapies. In this paper, we discuss the role of radionuclide imaging in the evaluation and management of patients with the most common form of amyloidosis—cardiac transthyretin amyloidosis (ATTR). We provide a comprehensive summary of the literature interspersed with our institutional experience as appropriate, to deliver our perspective.

ObjectiveTo determine the value of [F-18]PBR06-PET for assessment of microglial activation in the cerebral gray matter in patients with MS.MethodsTwelve patients with MS (7 relapsing-remitting and 5 secondary progressive [SP]) and 5 healthy controls (HCs) had standardized uptake value (SUV) PET maps coregistered to 3T MRI and segmented into cortical and subcortical gray matter regions. SUV ratios (SUVRs) were global brain normalized. Voxel-by-voxel analysis was performed using statistical parametric mapping (SPM). Normalized brain parenchymal volumes (BPVs) were determined from MRI using SIENAX.ResultsCortical SUVRs were higher in the hippocampus, amygdala, midcingulate, posterior cingulate, and rolandic operculum and lower in the medial-superior frontal gyrus and cuneus in the MS vs HC group (allp< 0.05). Subcortical gray matter SUVR was higher in SPMS vs RRMS (+10.8%,p= 0.002) and HC (+11.3%,p= 0.055) groups. In the MS group, subcortical gray matter SUVR correlated with the Expanded Disability Status Scale (EDSS) score (r = 0.75,p= 0.005) and timed 25-foot walk (T25FW) (r = 0.70,p= 0.01). Thalamic SUVRs increased with increasing EDSS scores (r = 0.83,p= 0.0008) and T25FW (r = 0.65,p= 0.02) and with decreasing BPV (r = −0.63,p= 0.03). Putaminal SUVRs increased with increasing EDSS scores (0.71,p= 0.009) and with decreasing BPV (r = −0.67,p= 0.01). On SPM analysis, peak correlations of thalamic voxels with BPV were seen in the pulvinar and with the EDSS score and T25FW in the dorsomedial thalamic nuclei.ConclusionsThis study suggests that [F-18]PBR06-PET detects widespread abnormal microglial activation in the cerebral gray matter in MS. Increased translocator protein binding in subcortical gray matter regions is associated with brain atrophy and may link to progressive MS.

Purpose: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations of the TSC1 or TSC2 gene, characterized by neurocognitive impairment and benign tumors of the brain, skin, heart, and kidneys. Lymphangioleiomyomatosis (LAM) is a diffuse proliferation of α-smooth muscle actin–positive cells associated with cystic destruction of the lung. LAM occurs almost exclusively in women, as a TSC manifestation or a sporadic disorder (TSC1/TSC2 somatic mutations). Biomarkers of whole-body tumor burden/activity and response to rapalogs or other therapies remain needed in TSC/LAM. Experimental Design: These preclinical studies aimed to assess feasibility of [18F]fluorocholine (FCH) and [18F]fluoroacetate (FACE) as TSC/LAM metabolic imaging biomarkers. Results: We previously reported that TSC2-deficient cells enhance phosphatidylcholine synthesis via the Kennedy pathway. Here, we show that TSC2-deficient cells exhibit rapid uptake of [18F]FCH in vivo and can be visualized by PET imaging in preclinical models of TSC/LAM, including subcutaneous tumors and pulmonary nodules. Treatment with rapamycin (72 hours) suppressed [18F]FCH standardized uptake value (SUV) by >50% in tumors. Interestingly, [18F]FCH-PET imaging of TSC2-deficient xenografts in ovariectomized mice also showed a significant decrease in tumor SUV. Finally, we found rapamycin-insensitive uptake of FACE by TSC2-deficient cells in vitro and in vivo, reflecting its mitochondrial accumulation via inhibition of aconitase, a TCA cycle enzyme. Conclusions: Preclinical models of TSC2 deficiency represent informative platforms to identify tracers of potential clinical interest. Our findings provide mechanistic evidence for testing the potential of [18F]FCH and [18F]FACE as metabolic imaging biomarkers for TSC and LAM proliferative lesions, and novel insights into the metabolic reprogramming of TSC tumors.

Importance Cardiac amyloidosis is an underdiagnosed disease and is highly fatal when untreated. Early diagnosis and treatment with the emerging novel therapies significantly improve survival. A comprehensive analysis of amyloidosis-related mortality is critical to appreciate the nature and distribution of underdiagnosis and improve disease detection. Objective To evaluate the temporal and regional trends in age-adjusted amyloidosis-related mortality among men and women of various races/ethnicities in the United States. Design, Setting, and Participants In this observational cohort study, death certificate information from the Centers for Disease Control and Prevention’s Wide-ranging ONline Data for Epidemiologic Research database and the National Vital Statistics System from 1979 to 2015 was analyzed. A total of 30 764 individuals in the United States with amyloidosis listed as the underlying cause of death and 26 591 individuals with amyloidosis listed as a contributing cause of death were analyzed. Exposures Region of residence. Main Outcomes and Measures Age-adjusted mortality rate from amyloidosis per 1 000 000 population stratified by year, sex, race/ethnicity, and state and county of residence. Results Of the 30 764 individuals with amyloidosis listed as the underlying cause of death, 17 421 (56.6%) were men and 27 312 (88.8%) were 55 years or older. From 1979 to 2015, the reported overall mean age-adjusted mortality rate from amyloidosis as the underlying cause of death doubled from 1.77 to 3.96 per 1 000 000 population (2.32 to 5.43 in men and 1.35 to 2.80 in women). Black men had the highest mortality rate (12.36 per 1 000 000), followed by black women (6.48 per 1 000 000). Amyloidosis contributed to age-adjusted mortality rates as high as 31.73 per 1 000 000 in certain counties. Most southern states reported the lowest US mortality rates despite having the highest proportions of black individuals. Conclusions and Relevance The increased reported mortality over time and in proximity to amyloidosis centers more likely reflects an overall increase in disease diagnosis rather than increased lethality. The reported amyloidosis mortality is highly variable in different US regions. The lack of higher reported mortality rates in states with a greater proportion of black residents suggests underdiagnosis of amyloidosis, including cardiac forms of the disease, in many areas of the United States. Better understanding of the determinants of geographic and racial disparity in the reporting of amyloidosis deaths are warranted.

BACKGROUND AND PURPOSE F-PBR06 and C-PBR28 are second-generation PET radioligands targeting the 18-kd translocator protein to assess microglial activation. We directly compared F-PBR06 and C-PBR28 for detecting brain translocator protein binding in multiple sclerosis (MS). METHODS Six patients with MS (4 women; mean age ± SD, 32.1 ± 4.9 [range, 23.5-37.4 years]; Expanded Disability Status Scale score 2.3 ± 1.2 [range, 1.0-4.0]) underwent brain PET with both ligands, along with 3-T MRI. MRI was coregistered to the summed 60- to 90-minute PET images. SUV ratios (SUVRs), derived by normalization to global brain radioactivity, were obtained for whole-brain white matter (WM), supratentorial WM, normal-appearing WM (NAWM), and T2 (fluid-attenuated inversion recovery) hyperintense and T1 hypointense MS WM lesions. The highest mean SUVR for the fluid-attenuated inversion-recovery lesional slices was defined as SUVRmax. RESULTS F-PBR06 and C-PBR28 were moderately intercorrelated for whole-brain WM SUVR (r = 0.83, P = 0.04) and supratentorial WM SUVR (r = 0.81, P = 0.05) but not for SUVRs of NAWM, T1 lesions, T2 lesions, or SUVRmax. Both tracers demonstrated that SUVR was higher in NAWM than in T1 and T2 lesions (all P < 0.05). F-PBR06 (but not C-PBR28) demonstrated a higher SUVR in T1 versus T2 lesions (0.85 ± 0.07 vs 0.78 ± 0.03, P = 0.03). F-PBR06-derived (but not C-PBR28) SUVRmax correlated with both Expanded Disability Status Scale score (r = 0.82, P = 0.04) and timed 25-ft walking speed (r = 0.89, P = 0.01). CONCLUSIONS Our preliminary results suggest an association between microglial activation and physical disability in MS. Microglial detection in lesions was not interchangeable between the tracers, with a higher clinical relevance suggested for F-PBR06.

Relative apical sparing of strain (RAS) is a typical echocardiographic (Echo) feature of transthyretin amyloid cardiomyopathy (ATTR-CM). Cardiac magnetic resonance (CMR) is widely used to evaluate myocardial characteristics. CMR feature-tracking is now available to evaluate strain. The aim of this

Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are becoming increasingly important for the diagnosis and staging of brain tumors, as well as for the monitoring of response to therapy. The purpose of these imaging modalities is to estimate the distribution of a radiotracer from external measurements of the pattern of photons emerging from the brain. In this chapter, the physics underlying the generation of these photons will be described. A great deal of effort has been expended in the design of SPECT and PET instrumentation, leading to major advances in this area. The major scanner configurations, as well as the instrument design considerations, are discussed. Images must be mathematically reconstructed from the external measurements; the techniques used to accomplish this while correcting for physical effects that degrade the accuracy and precision of the measurements are outlined.

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.

Sensitivity near the center of the brain is critical for some clinical applications of brain SPECT, especially for those applications which require dynamic imaging. We have designed and built a novel collimator for the CeraSPECT dedicated brain SPECT system which uses variable focusing to increase the sensitivity for central regions of its field of view. The sensitivity at the center of the field of view is increased by a factor of two compared to the standard three-segment parallel-hole collimator; this sensitivity gain is achieved without compromising spatial resolution

We assessed improvements in performance in detection and estimation tasks due to a novel brain single photon computed tomography collimator. Data were acquired on the CeraSPECT{sup TM} scanner using both new and standard collimators. The new variable focusing collimator SensOgrade{sup TM} samples the projections unequally, with central regions more heavily represented, to compensate for attenuation of counts from central brain structures. Furthermore, it utilizes more of the cylindrical crystal surface. Two phantom studies were performed. The first phantom was a 21-cm-diameter cylindrical background containing nine spheres ranging from 0.5 to 5 cm{sup 3} in volume. {sup 99m}Tc sphere to background activity ratio was 10:1. Twenty-nine 10-min datasets were acquired with each collimator. The second phantom was the Radiology Support Devices (Long Beach, CA) striatal phantom with striatal-background ratios of 10:1 on the left and 5:1 on the right. Twenty-nine 4-min datasets were acquired with each collimator. Perfusion imaging using {sup 99m}Tc-HMPAO was also performed in three healthy volunteers using both collimators under identical simulations. Projections were reconstructed by filtered backprojection with an unwindowed ramp filter. The nonprewhitening matched filter signal-to-noise ratio (NPW-SNR) was computed as a surrogate for human performance in detecting spherical lesions. Sphere activity concentration, radius, and locationmore » coordinates were simultaneously estimated by fitting images to an assumed model using an iterative nonlinear algorithm. Resolution recovery was implicit in the estimation procedure, as the point spread function was incorporated into the model. NPW-SNR for sphere detection was 1.5 to 2 times greater with the new collimator; for the striatal phantom the improvement in SNR was 54%. The SNR for estimating sphere activity concentration improved by 46 to 89 % for spheres located more than 5 cm from the phantom center. Images acquired with the standard collimator were too noisy in the central regions to allow estimation of sphere activity. In {sup 99m}Tc-HMPAO human studies, SNR was improved by 21 to 41 % in the cortex, 66% in the basal ganglia, and 74% in the thalamus. The new collimator leads to substantially improved detection and estimation performance throughout the brain. The higher sensitivity will be particularly important for dynamic imaging.« less

We describe a new approach to the problem of collimator optimization in nuclear medicine; our methodology is illustrated for the challenging case of gallium-67 imaging. Collimator-design methods based on empirical rules, such as specification of an allowable level of single-septal penetration (SSP) at a fixed energy, are especially inappropriate for radionuclides characterized by an abundance of high-energy contaminant photons that scatter in the patient, collimator, and/or detector before detection within one of a few photopeak energy windows. Lead X-rays produced in the collimator are an additional source of contamination. We designed optimal collimation for /sup 67/Ga based on relevant clinical imaging tasks and a realistic simulation of photon transport in a phantom, collimator, and detector. Collimator designs were compared on the basis of performance in lesion detection, as predicted by a three-channel Hotelling observer (CHO), as well as in tumor and background activity estimation (EST), quantified by task-specific signal-to-noise ratios (SNRs). The optimal values of collimator lead content were 22.0 and 23.8 g/cm/sup 2/, respectively, for CHO and EST, while the optimal geometric resolution values were 1.8 and 1.6 cm full-width at half-maximum (FWHM), respectively, at a distance of 23.5 cm. The resolution of a commercially available medium-energy low-penetration collimator (MELP) is 1.9 cm FWHM at this distance. The optimal values for SSP at 300 keV were 7.3% and 5.8% based on CHO and EST, respectively, compared to 5.2% for the MELP collimator. Compared with the commercial MELP collimator, the /sup 67/Ga collimator optimized for tumor detection or activity estimation tasks provided improved geometric spatial resolution with reduced geometric efficiency and, surprisingly, allowed an increased level of single-septal penetration.

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.

Compton scatter, lead X-rays, and high-energy contamination are major factors affecting image quality in Ga-67 imaging. Scattered photons detected in one photopeak window include photons exiting the patient at energies within the photopeak, as well as higher energy photons which have interacted in the collimator and crystal and lost energy. Furthermore, lead X-rays can be detected in the main energy photopeak (93 keV). We have previously developed two energy-based methods, based on artificial neural networks (ANN) and on a generalized spectral (GS) approach to compensate for scatter, high-energy contamination, and lead X-rays in Ga-67 imaging. For comparison, we considered also the projections that would be acquired in the clinic using the optimal energy windows (WIN) we have reported previously for tumor detection and estimation tasks for the 93, 185, and 300 keV photopeaks. The aim of the present study is to evaluate under realistic conditions the impact of these phenomena and their compensation on tumor detection and estimation tasks in Ga-67 imaging. ANN and GS were compared on the basis of performance of a three-channel Hotelling observer (CHO), in detecting the presence of a spherical tumor of unknown size embedded in an anatomic background as well as on the basis of estimation of tumor activity. Projection datasets of spherical tumors ranging from 2 to 6 cm in diameter, located at several sites in an anthropomorphic torso phantom, were simulated using a Monte Carlo program that modeled all photon interactions in the patient as well as in the collimator and the detector for all decays between 91 and 888 keV. One hundred realistic noise realizations were generated from each very-low-noise simulated projection dataset. The presence of scatter degraded both CHO signal-to-noise ratio (SNR) and estimation accuracy. On average, the presence of scatter led to a 12% reduction in CHO SNR. Correcting for scatter further diminished CHO SNR but to a lesser extent with ANN (5% reduction) than with GS (12%). Both scatter corrections improved performance in activity estimation. ANN yielded better precision (1.8% relative standard deviation) than did GS (4%) but greater average bias (5.1% with ANN, 3.6% with GS).

Simultaneous dual isotope imaging (/sup 99m/Tc//sup 123/I) has potential clinical applications but has not been implemented in the clinic. The aim of this work was to design an artificial neural network (ANN) for crosstalk and scatter correction using a smaller number of energy windows (8) than we had previously proposed (26) to allow implementation on some clinical cameras, and to validate our approach using realistic Monte Carlo simulations and anthropomorphic brain phantom acquisitions. Monte Carlo simulations of dual isotope SPECT studies of a digital brain phantom and physical acquisitions of the striatal brain phantom were used to validate our approach. Corrected projections were reconstructed using an iterative ordered subsets expectation maximization (OSEM) algorithm that modeled nonuniform attenuation and variable collimator response in the projector/backprojector. Results: In Monte Carlo simulations, ANN26 and ANN8 yielded similarly accurate quantitation of /sup 123/I activity (bias

The authors assessed the potential performance of three commercial SPECT systems in simulated, but realistic, imaging tasks related to the diagnosis and management of Parkinson's disease (PD). Images of I-123 altropane activity distributions in normal and PD brains were modeled assuming values from the literature for striatal sizes and activity concentrations, as well as for nonspecific activity. Imaging characteristics of the three systems were determined by phantom studies. The expected distributions of estimates of activity concentration and striatal volume were based on covariance matrices determined by the Cramer-Rao lower bounds calculated for a simultaneous estimation of these two parameters, as well as background activity concentration. Potential performance in several binary classification tasks was assessed by fitting ROC curves to simulated likelihood ratios for 5000 'subjects' in each category. For all conditions studied, ROC areas were similar for the higher-resolution instruments and lower for the lower-resolution system. These results imply a diagnostic advantage for higher-resolution systems in imaging tasks related to PD.

Estimates of SPECT activity within certain deep brain structures could be useful for clinical tasks such as early prediction of Alzheimer's disease with Tc-99m or Parkinson's disease with I-123; however, such estimates are biased by poor spatial resolution and inaccurate scatter and attenuation corrections. We compared an analytical approach (AA) of more accurate quantitation to a slower iterative approach (IA). Monte Carlo simulated projections of 12 normal and 12 pathologic Tc-99m perfusion studies, as well as 12, normal and 12 pathologic I-123 neurotransmission studies, were generated using a digital brain phantom and corrected for scatter by a multispectral fitting procedure. The AA included attenuation correction by a modified Metz-Fan algorithm and activity estimation by a technique that incorporated Metz filtering to compensate for variable collimator response (VCR), IA-modeled attenuation, and VCR in the projector/backprojector of an ordered subsets-expectation maximization (OSEM) algorithm. Bias and standard deviation over the 12 normal and 12 pathologic patients were calculated with respect to the reference values in the corpus callosum, caudate nucleus, and putamen. The IA and AA yielded similar quantitation results in both Tc-99m and I-123 studies in all brain structures considered in both normal and pathologic patients. The bias with respect to the reference activity distributions was less than 7% for Tc-99m studies, but greater than 30% for I-123 studies, due to partial volume effect in the striata. Our results were validated using I-123 physical acquisitions of an anthropomorphic brain phantom. The IA yielded quantitation accuracy comparable to that obtained with IA, while requiring much less processing time. However, in most conditions, IA yielded lower noise for the same bias than did AA.

Three algorithms for scatter compensation in Tc-99m brain single-photon emission computed tomography (SPECT) were optimized and compared on the basis of the accuracy and precision with which lesion and background activity could be simultaneously estimated. These performance metrics are directly related to the clinically important tasks of activity quantitation and lesion detection, in contrast to measures based solely on the fidelity of image pixel values. The scatter compensation algorithms were (a) the Compton-window (CW) method with a 20% photopeak window, a 92-126 keV scatter window, and an optimized "k-factor," (b) the triple-energy window (TEW) method, with optimized widths of the photopeak window and the abutting scatter window, and (c) a general spectral (GS) method using seventeen 4 keV windows with optimized energy weights. Each method was optimized by minimizing the sum of the mean-squared errors (MSE) of the estimates of lesion and background activity concentrations. The accuracy and precision of activity estimates were then determined for lesions of different size, location, and contrast, as well as for a more complex Bayesian estimation task in which lesion size was also estimated. For the TEW and GS methods, parameters optimized for the estimation task differed significantly from those optimized for global normalized pixel MSE. For optimal estimation, the CW bias of activity estimates was larger and varied more (-2% to 22%) with lesion location and size than that of the other methods. The magnitude of the TEW bias was less than 7% across most conditions, although its precision was worse than that of CW estimates. The GS method performed best, with bias generally less than 4% and the lowest variance; its root-mean square (rms) estimation error was within a few percent of that achievable from primary photons alone. For brain SPECT, estimation performance with an optimized, energy-based, subtractive correction may approach that of an ideal scatter-rejection procedure.

Simultaneous imaging of Tc-99m and I-123 would have a high clinical potential in the assessment of brain perfusion (Tc-99m) and neurotransmission (I-123) but is hindered by cross-talk between the two radionuclides. Monte Carlo simulations of 15 different dual-isotope studies were performed using a digital brain phantom. Several physiologic Tc-99m and I-123 uptake patterns were modeled in the brain structures. Two methods were considered to correct for cross-talk from both scattered and unscattered photons: constrained spectral factor analysis (SFA) and artificial neural networks (ANN). The accuracy and precision of reconstructed pixel values within several brain structures were compared to those obtained with an energy windowing method (WSA). In I-123 images, mean bias was close to 10% in all structures for SFA and ANN and between 14% (in the caudate nucleus) and 25% (in the cerebellum) for WSA. Tc-99m activity was overestimated by 35% in the cortex and 53% in the caudate nucleus with WSA, but by less than 9% in all structures with SFA and ANN. SFA and ANN performed well even in the presence of high-energy I-123 photons. The accuracy was greatly improved by incorporating the contamination into the SFA model or in the learning phase for ANN. SFA and ANN are promising approaches to correct for cross-talk in simultaneous Tc-99m/I-123 SPECT.

Describes a method to estimate unattenuated projection images directly from Ga-67 SPECT data acquired over 360/spl deg/ at three photopeak energies. The algorithm compensates to third order for the effects of nonuniform attenuation, thereby yielding unattenuated projections with

Lyme encephalopathy (LE) presents with subtle neuropsychiatric symptoms months to years after onset of infection with Borrelia burgdorferi. Brain magnetic resonance images are usually normal. We asked whether quantitative single photon emission computed tomography (SPECT) is a useful method to diagnose LE, to measure the response to antibiotic therapy, and to determine its neuroanatomic basis. In 13 patients with objective evidence of LE, SPECT demonstrated reduced cerebral perfusion (mean perfusion defect index [PDI] = 255), particularly in frontal subcortical and cortical regions. Six months after treatment with 1 month of intravenous ceftriaxone, perfusion significantly improved in all 13 patients (mean PDI = 188). In nine patients with neuropsychiatric symptoms following Lyme disease, but without objective abnormalities (e.g., possible LE), perfusion was similar to that of the treated LE group (mean PDI = 198); six possible LE patients (67%) had already received ceftriaxone prior to our evaluation. Perfusion was significantly lower in patients with LE and possible LE than in 26 normal subjects (mean PDI = 136), but 4 normal subjects (15%) had low perfusion in the LE range. We conclude that LE patients have hypoperfusion of frontal subcortical and cortical structures that is partially reversed after ceftriaxone therapy. However, SPECT cannot be used alone to diagnose LE or determine the presence of active CNS infection.

We believe that image-guided therapy is slowly but surely moving into a new phase: molecular imaging (MI)-guided therapy. MI-guided surgeries and interventions require validated MI imaging agents, and the presence of a PET/CT system in the AMIGO suite gives us a unique platform for in vivo human validation of these agents, at present primarily for brain and prostate cancer but eventually for other malignancies. Multiple pathological samples from open brain surgery or prostate biopsies will be acquired and compared to PET data from corresponding image locations. Very precise mapping of sampling sites to image locations will be possible. This capability will make possible the much-needed translational steps for the validation of new tumor localizing and characterizing MI agents. Accurately defined tumor extent can guide the radiologist or interventional radiologist to achieve full or maximal resection or ablation. Using this technology, physicians can localize and target viable tumor tissue before the procedures and ensure the complete removal or destruction of tumors by visualizing any residual cancer tissue before concluding the procedure. The combined use of MRI and CT with PET enables clinicians to integrate anatomical, functional, and metabolic information to guide their decision-making during tumor resections and percutaneous thermal ablations.

The authors have previously reported the advantages of high-sensitivity single-photon emission computed tomography (SPECT) systems for imaging structures located deep inside the brain. DaTscan (Isoflupane I-123) is a dopamine transporter (DaT) imaging agent that has shown potential for early detection of Parkinson disease (PD), as well as for monitoring progression of the disease. Realizing the full potential of DaTscan requires efficient estimation of striatal uptake from SPECT images. They have evaluated two SPECT systems, a conventional dual-head gamma camera with low-energy high-resolution collimators (conventional) and a dedicated high-sensitivity multidetector cardiac imaging system (dedicated) for imaging tasks related to PD.Cramer-Rao bounds (CRB) on precision of estimates of striatal and background activity concentrations were calculated from high-count, separate acquisitions of the compartments (right striata, left striata, background) of a striatal phantom. CRB on striatal and background activity concentration were calculated from essentially noise-free projection datasets, synthesized by scaling and summing the compartment projection datasets, for a range of total detected counts. They also calculated variances of estimates of specific-to-nonspecific binding ratios (BR) and asymmetry indices from these values using propagation of error analysis, as well as the precision of measuring changes in BR on the order of the average annual decline in early PD.Under typical clinical conditions, the conventional camera detected 2 M counts while the dedicated camera detected 12 M counts. Assuming a normal BR of 5, the standard deviation of BR estimates was 0.042 and 0.021 for the conventional and dedicated system, respectively. For an 8% decrease to BR = 4.6, the signal-to-noise ratio were 6.8 (conventional) and 13.3 (dedicated); for a 5% decrease, they were 4.2 (conventional) and 8.3 (dedicated).This implies that PD can be detected earlier with the dedicated system than with the conventional system; therefore, earlier identification of PD progression should be possible with the high-sensitivity dedicated SPECT camera.

The advantages of simultaneous acquisition of Tc-99m and Tl-201 myocardial perfusion SPECT images can be fully realized only if the effects of the Tc-99m agent can be accurately removed from the Tl-201 image. The authors and others have previously reported simultaneous dual-isotope techniques for cardiac studies which make use of a third energy-window to estimate the Tc-99m scatter to be subtracted from the Tl-201 window. The authors have recently demonstrated, however, using a Monte Carlo program which simulates all details of the photon transport, that lead X-rays produced in the collimator may also contribute significantly to contamination in the Tl-201 window. The spatial distribution of the Tc-99m scattered photons differs from that of the lead X-rays. Therefore, the authors modified their correction technique so that, at each projection angle, the contaminant image to be subtracted from the image in the Tl-201 window was estimated as a linear combination of a scatter-window (90-110 keV) image, blurred by a 2D Gaussian filter, and the Tc-99m photopeak image, blurred by a different Gaussian filter. For simulated data which included 'liver' activity and non-uniform 'lung' attenuation, the improved dual-window subtraction technique provided a more accurate estimate of the true Tl-201 image, with less image noise, than did the single-window correction. >

A Bayesian estimator has been developed as a paradigm for human observer performance in detecting lesions of unknown size in a uniform noisy background. The Bayesian observer used knowledge of the range of possible lesion sizes as a prior; its predictions agreed well with the results of a six-observer perceptual study. The average human response to changes in collimator resolution, as measured by the detectability index, dA, was tracked by the Bayesian detector's signal-to-noise ratio (SNR) somewhat better than by two other estimation models based, respectively, on lesser and greater degrees of lesion size uncertainty. As the range of possible lesion sizes increased, the Bayesian detector's SNR decreased and the optimal collimator resolution shifted towards better resolution. An analytic approximation for the variance of lesion activity estimates (which included the same prior) was shown to predict the variance of the Bayesian estimator over a wide range of collimator resolution values. Because the bias of the Bayesian estimator was small (1%), the analytic variance estimate permitted a rapid and convenient prediction of the Bayesian detection SNR. This calculation was then used to optimize the geometric parameters of a two-layer tungsten collimator being constructed from crossed grids for a new imaging detector. A Monte Carlo program was first run to estimate all contributions to the radial point-spread function for collimators of differing tungsten contents and spatial resolution values, imaging 140-keV photons emitted from the center of a 15-cm-diameter, water-filled attenuator. The optimal collimator design for detecting lesions with unknown diameters in the range 2.5-7.5 mm yielded a system resolution of approximately 8.5-mm FWHM, a geometric collimator efficiency of 1.21 x 10(-4), and a single-septum penetration probability of 1%.