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Background: In light-chain (AL) amyloidosis, whether functional status and heart failure-related quality of life (HF-QOL) correlate with cardiomyopathy severity, improve with therapy, and are associated with major adverse cardiac events (MACE) beyond validated scores is not well-known., Objectives: The authors aimed to: 1) correlate functional status and HF-QOL with cardiomyopathy severity; 2) analyze their longitudinal changes; and 3) assess their independent associations with MACE., Methods: This study included 106 participants with AL amyloidosis, with 81% having AL cardiomyopathy. Functional status was evaluated using the NYHA functional class, the Karnofsky scale, and the 6-minute walk distance (6MWD), and HF-QOL using the MLWHFQ (Minnesota Living with Heart Failure Questionnaire). Cardiomyopathy severity was assessed by cardiac 18 F-florbetapir positron emission tomography/computed tomography, cardiac magnetic resonance, echocardiography, and serum cardiac biomarkers. MACE were defined as all-cause death, heart failure hospitalization, or cardiac transplantation., Results: NYHA functional class, Karnofsky scale, 6MWD, and MLWHFQ were impaired substantially in participants with recently diagnosed AL cardiomyopathy (P < 0.001), and correlated with all markers of cardiomyopathy severity (P ≤ 0.010). NYHA functional class, 6MWD, and MLWHFQ improved at 12 months in participants with cardiomyopathy (P ≤ 0.013). All measures of functional status and HF-QOL were associated with MACE (P ≤ 0.017), independent of Mayo stage for 6MWD and MLWHFQ (P ≤ 0.006)., Conclusions: Functional status and HF-QOL were associated with AL cardiomyopathy severity, improved on therapy within 12 months, and were associated with MACE, independently of Mayo stage for 6MWD and MLWHFQ. They may be validated further in addition to prognostic scores and as surrogate outcomes for future studies., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health (NIH) (NCT02641145). Dr Clerc has received a research fellowship from the International Society of Amyloidosis and Pfizer. Dr Vijayakumar has received a research fellowship from the Amyloidosis Foundation. Dr Cuddy is supported by NIH 1K23HL166686-01 and AHA 23CDA857664; has received an investigator-initiated research grant from Pfizer; and has received consulting fees from Ionis Pharmaceuticals, AstraZeneca, BridgeBio, and Novo Nordisk. Dr Bianchi was partially supported by a grant K08 CA245100; and has received consulting fees from Prothena. Dr Benz has received investigator-initiated funding from AstraZeneca; and has received consulting fees from Pfizer and travel support from Philips Research and Pfizer. Dr Yee has received consulting fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Regeneron, Sanofi, and Takeda. Dr Ruberg is supported by NIH R01 HL 130563; has received consulting fees from Pfizer, AstraZeneca, and Attralus; and has received research support to his institution from Pfizer, Alnylam, Anumana, and Ionis/Akcea. Dr Liao is supported by NIH AHA16 CSA 2888 0004 and AHA19SRG34950011. Dr Falk is supported by NIH R01 HL 130563; has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences; and has received research funding from GlaxoSmithKline and Akcea. Dr Sanchorawala has received research support from Takeda, Celgene, Janssen, and Prothena; and is a scientific advisory board member for Caleum Biosciences. Dr Dorbala is supported by NIH R01 HL 130563, K24 HL 157648, AHA16 CSA 2888 0004, and AHA19SRG34950011; has received consulting fees from Pfizer, GE Health Care, AstraZeneca, and Novo Nordisk; and has received investigator-initiated grant from Pfizer, GE Healthcare, Attralus, Siemens, and Philips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In systemic light-chain (AL) amyloidosis, cardiac involvement portends poor outcomes., Objectives: The authors' objectives were to detect early myocardial alterations, to analyze longitudinal changes with therapy, and to predict major adverse cardiac events (MACE) in participants with AL amyloidosis using cardiac magnetic resonance imaging (MRI)., Methods: Recently diagnosed participants were prospectively enrolled. AL amyloidosis with and without cardiomyopathy (AL-CMP, AL-non-CMP) were defined based on abnormal cardiac biomarkers and wall thickness. MRI was performed at baseline, 6 months in all participants, and 12 months in participants with AL-CMP. MACE were defined as all-cause death, heart failure hospitalization, and cardiac transplantation. Mayo stage was based on troponin T, N-terminal pro-B-type natriuretic peptide, and difference in free light chains., Results: This study included 80 participants (median age 62 years, 58% men). Extracellular volume (ECV) was abnormal (>32%) in all participants with AL-CMP and in 47% of those with AL-non-CMP. ECV tended to increase at 6 months (median +2%; AL-CMP P = 0.120; AL-non-CMP P = 0.018) and returned to baseline values at 12 months in participants with AL-CMP. Global longitudinal strain (GLS) improved at 6 months (median -0.6%; P = 0.048) and 12 months (median -1.2%; P < 0.001) in participants with AL-CMP. ECV and GLS were strongly associated with MACE (P < 0.001) and improved the prognostic value when added to Mayo stage (P ≤ 0.002). No participant with ECV ≤32% had MACE, while 74% of those with ECV >48% had MACE., Conclusions: In patients with systemic AL amyloidosis, ECV detects subclinical myocardial alterations. With therapy, ECV tends to increase at 6 months and returns to values unchanged from baseline at 12 months, whereas GLS improves at 6 and 12 months in participants with AL-CMP. ECV and GLS offer additional prognostic performance over Mayo stage. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145)., Competing Interests: Funding Support and Author Disclosures This work was supported by National Institutes of Health. Dr Dorbala was supported by grants R01 HL 130563, K24 HL 157648, AHA16 CSA 2888 0004, and AHA19SRG34950011. Dr Falk was supported by grant R01 HL 130563. Dr Liao was supported by grants AHA16 CSA 2888 0004 and AHA19SRG34950011. Dr Ruberg was supported by grants R01 HL 130563 and R01 HL 093148. Dr Cuddy was supported by grants NIH 1K23HL166686-01 and AHA 23CDA857664NIH. Dr Bianchi was partially supported by a grant K08 CA245100. Dr Clerc has received a research fellowship from the International Society of Amyloidosis and Pfizer. Dr Cuddy has received an investigator-initiated research grant from Pfizer, as well as consulting fees from BridgeBio, Ionis, Astra Zeneca and Novo Nordisk. Dr Bianchi has received consulting fees from Prothena. Dr Ruberg has received consulting fees from AstraZeneca and Attralus; and has received research support from Pfizer, Alnylam, Anumana, and Ionis/Akcea. Dr DiCarli has received a research grant from Spectrum Dynamics and Gilead; and has received consulting fees from Sanofi and General Electric. Dr Kwong has received grant funding from Alynlam Pharmaceuticals. Dr Falk has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences; and has received research funding from GlaxoSmithKline and Akcea. Dr Dorbala has received consulting fees from Pfizer, GE Healthcare, and Novo Nordisk; and has received investigator-initiated grants from Pfizer, GE Healthcare, Attralus, Siemens, and Phillips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Coronary microvascular dysfunction has been implicated in the development of hypertensive heart disease and heart failure, with subendocardial ischemia identified as a driver of sustained myocardial injury and fibrosis. We aimed to evaluate the relationships of subendocardial perfusion with cardiac injury, structure, and a composite of major adverse cardiac and cerebrovascular events consisting of death, heart failure hospitalization, myocardial infarction, and stroke., Methods: Layer-specific blood flow and myocardial flow reserve (MFR; stress/rest myocardial blood flow) were assessed by 13 N-ammonia perfusion positron emission tomography in consecutive patients with hypertension without flow-limiting coronary artery disease (summed stress score <3) imaged at Brigham and Women's Hospital (Boston, MA) from 2015 to 2021. In this post hoc observational study, biomarkers, echocardiographic parameters, and longitudinal clinical outcomes were compared by tertiles of subendocardial MFR (MFR subendo )., Results: Among 358 patients, the mean age was 70.6±12.0 years, and 53.4% were male. The median MFR subendo was 2.57 (interquartile range, 2.08-3.10), and lower MFR subendo was associated with older age, diabetes, lower renal function, greater coronary calcium burden, and higher systolic blood pressure ( P <0.05 for all). In cross-sectional multivariable regression analyses, the lowest tertile of MFR subendo was associated with myocardial injury and with greater left ventricular wall thickness and volumes compared with the highest tertile. Relative to the highest tertile, low MFR subendo was independently associated with an increased rate of major adverse cardiac and cerebrovascular events (adjusted hazard ratio, 2.99 [95% CI, 1.39-6.44]; P =0.005) and heart failure hospitalization (adjusted hazard ratio, 2.76 [95% CI, 1.04-7.32; P =0.042) over 1.1 (interquartile range, 0.6-2.8) years median follow-up., Conclusions: Among patients with hypertension without flow-limiting coronary artery disease, impaired MFR subendo was associated with cardiovascular risk factors, elevated cardiac biomarkers, cardiac structure, and clinical events., Competing Interests: B.W. reports consulting fees from Horizon Therapeutics, Kiniksa Pharmaceuticals, and Novo Nordisk. B.A. reports consulting fees from Spectrum Dynamics Medical. S. Dorbala reports grant support from Attralus, Pfizer, GE Healthcare, Phillips, and Siemens; S. Dorbala has consulted with Novo Nordisk and Alexion. R.B. reports research support from Amgen and Novartis and has consulted for Caristo Inc and Elucid Inc. P.J.S. reports consulting fees from Synektik, SA, research support from Siemens, and software royalties from Cedars-Sinai licensing. J.M.B. reports consulting fees from Bayer AG and AstraZeneca. M.F.D.C. reports grant support from Gilead Sciences, in-kind research support from Amgen, and consulting fees from MedTrace and Sanofi. The other authors report no conflicts.

Background: Quantitative technetium-99m-pyrophosphate cardiac single-photon emission computed tomography ( 99m Tc-PYP SPECT/CT) is an emerging method for estimating myocardial burden of transthyretin cardiac amyloidosis (ATTR-CA), but its efficacy in monitoring longitudinal changes remains uncertain. We aimed to investigate longitudinal changes in cardiac ATTR amyloid burden following transthyretin stabilization therapy using visual and quantitative 99m Tc-PYP SPECT/CT and to relate these with changes in cardiac biomarkers and function., Methods: This prospective longitudinal cohort study investigated changes in 99m Tc-PYP SPECT/CT in 23 participants with ATTR-CA on transthyretin stabilization therapy (median: 2.6 years). Quantitative analysis included left ventricular (LV) standardized uptake values (SUVs) (SUV max , SUV mean ), cardiac amyloid activity (CAA; SUV mean ∗LV activity volume), and percent injected dose (%ID) (mean activity concentration∗LV activity volume/injected activity), calculated using a threshold of >1.5 times left atrial blood pool activity concentration on SPECT/CT. Longitudinal changes of paired continuous and ordinal variables were analyzed using Wilcoxon signed-rank test., Results: Following therapy, visual grade decreased significantly (P = 0.003). Several quantitative 99m Tc-PYP metrics also decreased significantly: SUV max (median -0.75, P = 0.011), CAA (median: -406.6, P < 0.001), and %ID (median: -0.45, P < 0.001). Serum transthyretin levels improved (median: +6.5 mg/dL, P = 0.008). Echocardiographic parameters (global longitudinal strain, LV mass index, and LV wall thickness), N-terminal pro-B-type natriuretic peptide, and estimated glomerular filtration rate remained stable., Conclusions: Favorable changes in 99m Tc-PYP myocardial uptake were observed in participants on transthyretin stabilization therapy, whereas echocardiographic parameters and biomarkers remained stable. These results likely signify myocardial ATTR amyloid stabilization rather than amyloid burden regression. Further investigation is needed to understand the implications of these findings., (Copyright © 2024 American Society of Nuclear Cardiology. Published by Elsevier Inc. All rights reserved.)

Background: Positron emission tomography/computed tomography (PET/CT) with 18 F-florbetapir, a novel amyloid-targeting radiotracer, can quantify left ventricular (LV) amyloid burden in systemic light-chain (AL) amyloidosis. However, its prognostic value is not known., Objectives: The authors' aim was to evaluate the prognostic value of LV amyloid burden quantified by 18 F-florbetapir PET/CT, and to identify mechanistic pathways mediating its association with outcomes., Methods: A total of 81 participants with newly diagnosed AL amyloidosis underwent 18 F-florbetapir PET/CT imaging. Amyloid burden was quantified using 18 F-florbetapir LV uptake as percent injected dose. The Mayo stage for AL amyloidosis was determined using troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and free light chain levels. Major adverse cardiac events (MACE) were defined as all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months., Results: Among participants (median age, 61 years; 57% males), 36% experienced MACE, increasing from 7% to 63% across tertiles of LV amyloid burden (P < 0.001). LV amyloid burden was associated with MACE (HR: 1.46; 95% CI: 1.16-1.83; P = 0.001). However, this association became nonsignificant when adjusted for Mayo stage. In mediation analysis, the association between LV amyloid burden and MACE was mediated by NT-proBNP (P < 0.001), a marker of cardiomyocyte stretch and heart failure, and a component of Mayo stage., Conclusions: In this first study to link cardiac 18 F-florbetapir uptake to subsequent outcomes, LV amyloid burden estimated by percent injected dose predicted MACE in AL amyloidosis. This effect was not independent of Mayo stage and was mediated primarily through NT-proBNP. These findings provide novel insights into the mechanism linking myocardial amyloid deposits to MACE., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health. Dr Dorbala was supported by grants R01 HL 130563; K24 HL 157648; AHA16 CSA 2888 0004; AHA19SRG34950011. Dr Falk was supported by a grant R01 HL 130563. Dr Liao was supported by grants AHA16 CSA 2888 0004; AHA19SRG34950011. Dr Ruberg was supported by grants R01 HL 130563; R01 HL 093148. Dr Bianchi was partially supported by a grant K08 CA245100; and has received consulting fees from Prothena. Dr Clerc has received a research fellowship from the International Society of Amyloidosis and Pfizer. Dr Cuddy was supported by grants NIH 1K23HL166686-01 and AHA 23CDA857664NIH; and has received an investigator-initiated research grant from Pfizer; and has received consulting fees from BridgeBio, Ionis, AstraZeneca, and Novo Nordisk. Dr DiCarli has received a research grant from Gilead and Alnylam Pharmaceuticals; in-kind research support from Amgen; and consulting fees from Sanofi, MedTrace Pharma, and Valo Health. Dr Kwong has received grant funding from Alynlam Pharmaceuticals. Dr Falk has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, Caelum Biosciences; and research funding from GlaxoSmithKline and Akcea. Dr Ruberg has received consulting fees from AstraZeneca, and Attralus; and has received research support from Pfizer, Alnylam, Anumana, and Ionis/Akcea. Dr Dorbala has received consulting fees from Pfizer, GE Health Care, and Novo Nordisk; and investigator-initiated grants from Pfizer, GE Healthcare, Attralus, Siemens, and Philips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac systolic dysfunction is a poor prognostic marker in light-chain (AL) cardiomyopathy, a primary interstitial disorder; however, its pathogenesis is poorly understood., Purpose: This study aims to analyze the effects of extracellular volume (ECV) expansion, a surrogate marker of amyloid burden on myocardial blood flow (MBF), myocardial work efficiency (MWE), and left ventricular (LV) systolic dysfunction in AL amyloidosis., Methods: Subjects with biopsy-proven AL amyloidosis were prospectively enrolled (April 2016-June 2021; Clinicaltrials.gov ID NCT02641145) and underwent cardiac magnetic resonance imaging (MRI) to quantify rest MBF by perfusion imaging, LV ejection fraction (LVEF) by cine MRI, and ECV by pre- and post-contrast T1 mapping. The MWE was estimated as external cardiac work from the stroke volume and mean arterial pressure normalized to the LV myocardial mass., Results: Rest MBF in 92 subjects (62 ± 8 years, 52 men) with AL amyloidosis averaged 0.87 ± 0.21 ml/min/g and correlated with MWE ( r  = 0.42; p  < 0.001). Rest MBF was similarly low in subjects with sustained hematologic remission after successful AL amyloidosis therapy ( n  = 21), as in those with recently diagnosed AL amyloidosis. Both MBF and MWE decreased by ECV tertile ( p  < 0.01 for linear trends). The association of ECV with MWE comprised a direct effect (84% of the total effect; p  < 0.001) on MWE from adverse interstitial remodeling assessed by ECV and an indirect effect (16% of the total effect; p  < 0.001) mediated by MBF. There was a significant base-to-apex gradient of rest MBF in subjects with higher amyloid burden., Conclusions: In AL amyloidosis, both MBF and MWE decrease as cardiac amyloid burden and ECV expansion increase. Both structural and vascular changes from ECV expansion and myocardial amyloid burden appear to contribute to lower MWE., Competing Interests: SC: investigator—initiated a research grant from Pfizer. FR: consulting fees—Pfizer, AstraZeneca, Attralus; research support—Pfizer, Alnylam Pharmaceuticals, Akcea Therapeutics. MDC: research grant—Spectrum Dynamics and Gilead; consulting fees—Sanofi and GE HealthCare. RF: consulting fees—Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences; research funding—GlaxoSmithKline and Akcea. SD: consulting fees—Pfizer, GE HealthCare, and AstraZeneca; investigator—initiated a grant from Pfizer, Attralus, Phillips, and Siemens. OC: research fellowship from the International Society of Amyloidosis and Pfizer. AY: consulting fees—AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK Janssen, Karyopharm, Oncopeptides, Regeneron, Sanofi, and Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Katznelson, Jerosch-Herold, Cuddy, Clerc, Benz, Taylor, Rao, Kijewski, Liao, Landau, Yee, Ruberg, Di Carli, Falk, Kwong and Dorbala.)

Aims: In systemic light-chain (AL) amyloidosis, quantification of right ventricular (RV) amyloid burden has been limited and the pathogenesis of RV dysfunction is poorly understood. Using 18F-florbetapir positron emission tomography/computed tomography (PET/CT), we aimed to quantify RV amyloid; correlate RV amyloid with RV structure and function; determine the independent contributions of RV, left ventricular (LV), and lung amyloid to RV function; and associate RV amyloid with major adverse cardiac events (MACE: death, heart failure hospitalization, cardiac transplantation)., Methods and Results: We prospectively enrolled 106 participants with AL amyloidosis (median age 62 years, 55% males) who underwent 18F-florbetapir PET/CT, magnetic resonance imaging, and echocardiography. 18F-florbetapir PET/CT identified RV amyloid in 63% of those with and 40% of those without cardiac involvement by conventional criteria. RV amyloid burden correlated with RV ejection fraction (EF), RV free wall longitudinal strain (FWLS), RV wall thickness, RV mass index, N-terminal pro-brain natriuretic peptide, troponin T, LV amyloid, and lung amyloid (each P < 0.001). In multivariable analysis, RV amyloid burden, but not LV or lung amyloid burden, predicted RV dysfunction (EF P = 0.014; FWLS P < 0.001). During a median follow-up of 28 months, RV amyloid burden predicted MACE (P < 0.001)., Conclusion: This study shows for the first time that 18F-florbetapir PET/CT identifies early RV amyloid in systemic AL amyloidosis prior to alterations in RV structure and function. Increasing RV amyloid on 18F-florbetapir PET/CT is associated with worse RV structure and function, predicts RV dysfunction, and predicts MACE. These results imply a central role for RV amyloid in the pathogenesis of RV dysfunction., Competing Interests: Conflict of interest: O.F.C.: Research fellowship from the International Society of Amyloidosis and Pfizer. S.A.M.C.: Investigator-initiated research grant from Pfizer. A.J.Y.: Consulting fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Regeneron, Sanofi, and Takeda. V.S.: Research support from Takeda, Celgene, Janssen, and Prothena and scientific advisory board for Caelum Biosciences. F.L.R.: Consulting fees from AstraZeneca and research support from Pfizer, Alnylam, and Ionis/Akcea. H.L.: Consulting fees from Celgene, Takeda, Janssen, Prothena, Pfizer, and Juno and research support from Amgen, Spectrum, and Takeda. R.Y.K.: Grant funding from Alnylam Pharmaceuticals. M.F.D.C.: Research grant from Spectrum Dynamics and Gilead and consulting fees from Sanofi and General Electric. R.H.F.: Consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences and research funding from GlaxoSmithKline and Akcea. S.D.: Consulting fees from Pfizer and GE HealthCare and investigator-initiated grant from Pfizer, Attralus, GE HealthCare, Phillips, and Siemens. The other authors do not have any conflicts of interest related to this study to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cardiac amyloid quantification could advance early diagnosis of amyloid cardiomyopathy (CMP) and treatment monitoring. However, current imaging tools are based on indirect measurements. 124 I-evuzamitide is a novel pan-amyloid radiotracer binding to amyloid deposits from multiple amyloidogenic proteins. Its ability to quantify cardiac amyloid has not yet been investigated., Objectives: The objectives of this pilot study were to quantify myocardial 124 I-evuzamitide uptake and to compare its diagnostic value to 18 F-florbetapir in participants with amyloid CMP and control subjects., Methods: This study included 46 participants: 12 with light-chain (AL) CMP, 12 with wild-type transthyretin (ATTRwt) CMP, 2 with hereditary amyloidosis, and 20 control subjects. All amyloidosis participants underwent positron emission tomography/computed tomography with 124 I-evuzamitide and 18 F-florbetapir. Control subjects underwent 124 I-evuzamitide (n = 10) or 18 F-florbetapir (n = 8) positron emission tomography/computed tomography. Left ventricular percent injected dose (LV% ID) was measured as mean activity concentration × myocardial volume/injected activity. High LV %ID was defined using Youden's index., Results: In CMP participants, median age was 74 years and 92% were men. 124 I-evuzamitide LV %ID differed across groups: median AL-CMP 1.48 (IQR: 1.12-1.89), ATTRwt-CMP 2.12 (IQR: 1.66-2.47), and control subjects 0.00 (IQR: 0.00-0.01; overall P < 0.001). High LV %ID perfectly discriminated CMP from control subjects. Discrimination performance was similar for 18 F-florbetapir LV %ID. Notably, for ATTRwt-CMP, LV %ID was higher with 124 I-evuzamitide than 18 F-florbetapir (P = 0.002). 124 I-evuzamitide LV %ID was correlated with interventricular septum thickness (Spearman's ρ = 0.78) and LV global longitudinal strain (ρ = 0.54) from echocardiography, and with LV mass index (ρ = 0.82) and extracellular volume (ρ = 0.51) from cardiac magnetic resonance., Conclusions: 124 I-evuzamitide demonstrates uptake by cardiac amyloid and accurately discriminates amyloid CMP from control subjects. In AL-CMP, discrimination performance is similar to 18 F-florbetapir. In ATTRwt-CMP, performance may be better with 124 I-evuzamitide. Moderate-to-strong correlations of 124 I-evuzamitide uptake with cardiac structural and functional metrics suggest valid amyloid quantification. Hence, 124 I-evuzamitide is a promising novel radiotracer to detect and quantify cardiac amyloid., Competing Interests: Funding Support and Author Disclosures This work was supported by Attralus. Dr Clerc has received a research fellowship from the International Society of Amyloidosis and Pfizer. Dr Cuddy has received an investigator-initiated research grant from Pfizer; and has received consulting fees from Ionis Pharmaceuticals, AstraZeneca, BridgeBio, Novo Nordisk, and Pfizer. Dr Di Carli has received research grants from Spectrum Dynamics and Gilead; and has received consulting fees from Sanofi and General Electric. Dr Falk has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences; and has received research funding from GlaxoSmithKline and Akcea. Dr Dorbala is supported by National Institutes of Health K24HL157648; has received consulting fees from Pfizer, GE Healthcare, Novo Nordisk, and AstraZeneca; and has received investigator-initiated grants from Pfizer, Attralus, GE Healthcare, Philips, and Siemens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Myocardial infiltration by amyloid fibrils causes a severe and progressive form of heart failure. Until recently, this was not treatable. Several novel therapies have recently become available, increasing the urgency to make an accurate diagnosis, evaluate risk, and determine treatment response. Molecular imaging with positron-emitting amyloid tracers has a key emerging role in the evaluation and management of cardiac amyloidosis. In this review, we discuss molecular imaging of cardiac amyloidosis using amyloid PET tracers, including recent advances with a focus on the future., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Given the central importance of cardiorenal interactions, mechanistic tools for evaluating cardiorenal physiology are needed. In the heart and kidneys, shared pathways of neurohormonal activation, hypertension, and vascular and interstitial fibrosis implicate the relevance of systemic vascular health. The availability of a long axial field of view positron emission tomography (PET)/computed tomography (CT) system enables simultaneous evaluation of cardiac and renal blood flow., Methods: This study evaluated the feasibility of quantification of renal blood flow using data acquired during routine, clinically indicated 13 N-ammonia myocardial perfusion PET/CT. Dynamic PET image data were used to calculate renal blood flow. Reproducibility was assessed by the intraclass correlation coefficient among 3 independent readers. PET-derived renal blood flow was correlated with imaging and clinical parameters in the overall cohort and with histopathology in a small companion study of patients with a native kidney biopsy., Results: Among 386 consecutive patients with myocardial perfusion PET/CT, 296 (76.7%) had evaluable images to quantify renal perfusion. PET quantification of renal blood flow was highly reproducible (intraclass correlation coefficient 0.98 [95% CI, 0.93-0.99]) and was correlated with the estimated glomerular filtration rate ( r =0.64; P <0.001). Compared across vascular beds, resting renal blood flow was correlated with maximal stress myocardial blood flow and myocardial flow reserve (stress/rest myocardial blood flow), an integrated marker of endothelial health. In patients with kidney biopsy (n=12), resting PET renal blood flow was strongly negatively correlated with histological interstitial fibrosis ( r =-0.85; P <0.001)., Conclusions: Renal blood flow can be reliably measured from cardiac 13 N-ammonia PET/CT and allows for simultaneous assessment of myocardial and renal perfusion, opening a potential novel avenue to interrogate the mechanisms of emerging therapies with overlapping cardiac and renal benefits., Competing Interests: Disclosures Dr Brown reports consulting fees from Bayer. Dr Weber reports consulting fees from Horizon Therapeutics and Kiniksa Pharmaceuticals. Dr Dorbala reports unrelated grant support from Attralus, Pfizer, GE healthcare, and Phillips. Dr Blankstein reports research support from Amgen and Novartis and has consulted for Caristo Inc and Elucid Inc. Dr Di Carli reports grant support from Gilead Sciences, in-kind research support from Amgen, and consulting fees from MedTrace. The other authors report no conflicts.

Aim: The purpose of this study was to determine the inter- and intra-observer variability in 99m technetium-pyrophosphate ( 99m Tc-PYP) scan interpretation for diagnosis of transthyretin cardiac amyloidosis (ATTR)., Methods and Results: Our study cohort comprised 100 consecutive subjects referred for  99m Tc-PYP imaging based on clinical suspicion of ATTR cardiac amyloidosis. Myocardial  99m Tc-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  99m Tc-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 (r 2  = 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)., Conclusions: This study showed excellent inter-observer reproducibility and intra-observer repeatability of  99m Tc-PYP visual scan interpretation and H:CL ratio for diagnosis of cardiac ATTR amyloidosis. Cardiac ATTR amyloidosis can be diagnosed reliably using 99m Tc-PYP SPECT/CT by novice and experienced CV imagers., (© 2020. American Society of Nuclear Cardiology.)

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)., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health (to Dr Dorbala: R01 HL 130563, R01 HL 150342, AHA16 CSA 2888 0004, and K24 HL157648 AHA19SRG34950011; to Dr Falk: HL 130563; to Dr Liao: AHA16 CSA 2888 0004 and AHA19SRG34950011; to Dr Ruberg: HL 130563 and R01 HL 093148) (NCT02641145). Dr Cuddy has received an investigator-initiated research grant from Pfizer. Dr Singh has received a research grant from American Society of Nuclear Cardiology/Pfizer. Dr Ruberg has received consulting fees from Pfizer, GlaxoSmithKline, and Caleum Biosciences and research support from Eidos Therapeutics. Dr Sanchorawala has received research support from Takeda, Celgene, Janssen, and Prothena and has served on the Scientific Advisory Board for Caleum Biosciences. Dr Landau has received consulting fees from Celgene, Takeda, Janssen, Prothena, Pfizer, and Juno and research support from Amgen, Spectrum, and Takeda. Dr Maurer has received consulting income and his institution has received clinical trial funding from Pfizer, Eidos, Prothena, Akcea, and Alnylam. Dr Yee has received consulting fees from Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Sanofi, and Takeda. Dr Di Carli has received research grants from Spectrum Dynamics and Gilead and consulting fees from Sanofi and GE. Dr Falk has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences and research funding from GlaxoSmithKline and Akcea. Dr Dorbala has received consulting fees from Pfizer and GE Health Care; and her institution has received investigator-initiated grants from Pfizer, GE Healthcare, and Attralus. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (© 2022 Institute of Physics and Engineering in Medicine.)

Background: 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., Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 (clinical trials.gov NCT: 02641145). 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., (© 2019. American Society of Nuclear Cardiology.)

The primary aims of this study were to determine the correlation between absolute quantitative 99m Tc-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 99m Tc-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, SUV max , SUV mean , cardiac amyloid activity (CAA; i.e., SUV mean × 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. SUV max , SUV mean , 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, SUV max ). Intraobserver repeatability was excellent, with less than a 2% coefficient of variation for SUV max , %ID, and CAA and 3.8% for SUV mean 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 99m Tc-pyrophosphate cardiac imaging using a novel cadmium-zinc-telluride SPECT/CT scanner, SUV max , SUV mean , CAA, and %ID measured by absolute quantitation of 99m Tc-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., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Glioblastoma multiforme (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, we screened a d-peptide library to identify a small 8-amino acid dg- B can- T argeting P eptide (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, we radiolabeled BTP-7 with 18 F, a radioisotope of fluorine, and found increased radiotracer accumulation 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: The clinical diagnosis of pulmonary involvement in individuals with systemic AL amyloidosis remains challenging. [ 18 F]florbetapir imaging has previously identified AL amyloid deposits in the heart and extra-cardiac organs. The aim of this study is to determine quantitative [ 18 F]florbetapir pulmonary kinetics to identify pulmonary involvement in individuals with systemic AL amyloidosis., Methods: We prospectively enrolled 58 subjects with biopsy-proven AL amyloidosis and 9 control subjects (5 without amyloidosis and 4 with ATTR cardiac amyloidosis). Pulmonary [ 18 F]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)., Results: 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 < 0.001), TBR (median TBR 12.0 vs. 1.71, p < 0.001), and RI (median RI 0.310 vs. 0.033, p < 0.001) were substantially higher. Notably, the AL group without visually apparent pulmonary [ 18 F]florbetapir uptake also demonstrated a > 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 [ 18 F]florbetapir lung uptake was not related to [ 11 C]acetate lung uptake, suggesting that intense [ 18 F]florbetapir lung uptake represents AL amyloidosis rather than heart failure., Conclusions: [ 18 F]florbetapir PET/CT offers the potential to noninvasively identify pulmonary AL amyloidosis, and its clinical relevance warrants further study.

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 -11% (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)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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 [ 18 F]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.

Immunoglobulin light-chain (AL) amyloidosis affects multiple systemic organs. However, determination of the precise extent of organ involvement remains challenging. Targeted amyloid imaging with 18 F-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 18 F-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 18 F-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 SUV max 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 SUV max 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, 18 F-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 18 F-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: 18 F-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., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Objectives: 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 ( 18 F-florbetapir uptake by positron emission tomography [PET] and/or extracellular volume fraction [ECV] by cardiac magnetic resonance (CMR)]., Background: Further knowledge of the pathophysiological basis for RELAPS can help understand the adverse outcomes associated with apical LS impairment., Methods: 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 and 18 F-florbetapir PET for quantification of LV florbetapir retention index (RI). A subset also underwent CMR (n = 22) for ECV quantification. Extracellular LV mass (LV mass*ECV) and total florbetapir binding (extracellular LV mass*florbetapir RI) were also calculated. All parameters were measured globally and regionally (base, mid, and apex)., Results: There 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., Conclusions: 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., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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.

Objective: In MRI of patients with recurrent glioblastoma, bevacizumab-induced normalization of tumor vascularity can be difficult to differentiate from antitumor effects. The aim of this study was to assess the utility of 18 F-fluoroethyl-L-tyrosine (FET) PET in the evaluation of recurrent glioblastoma treated with bevacizumab., Subjects and Methods: MRI and FET PET were performed before and after administration of two doses of bevacizumab to 11 patients with recurrent glioblastoma. The ratio between normalized FET uptake at follow-up and baseline of the entire (volume of T2 FLAIR abnormality) and enhancing tumor were assessed for prediction of progression-free survival (PFS) and overall survival (OS). Voxel-wise Spearman correlation between normalized FET uptake and contrast-enhanced T1 signal intensity was assessed and tested as a predictor of PFS and OS., Results: Mean Spearman correlation between FET uptake and contrast-enhanced T1 signal intensity before therapy was 0.65 and after therapy was 0.61 (p = 0.256). The median PFS after initiation of bevacizumab therapy was 111 days, and the OS was 223 days. A post-treatment to pretreatment PET uptake ratio (mean and 90th percentile) greater than 0.7 for both entire and enhancing tumor was associated with lower PFS and OS (p < 0.001-0.049). The increase in correlation between PET uptake and contrast-enhanced T1 intensity after treatment was associated with lower PFS (p < 0.001) and OS (p = 0.049)., Conclusion: There is only a moderate correlation between FET PET uptake and contrast-enhanced T1 signal intensity. High posttreatment-to-pretreatment FET PET uptake ratio and increase in correlation between PET uptake and contrast-enhanced T1 signal intensity after bevacizumab treatment are associated with poor PFS and OS.

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 [ 18 F]fluorocholine (FCH) and [ 18 F]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 [ 18 F]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 [ 18 F]FCH standardized uptake value (SUV) by >50% in tumors. Interestingly, [ 18 F]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 [ 18 F]FCH and [ 18 F]FACE as metabolic imaging biomarkers for TSC and LAM proliferative lesions, and novel insights into the metabolic reprogramming of TSC tumors., (©2018 American Association for Cancer Research.)

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.

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.

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: 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., Methods: 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., Results: 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)., Conclusions: 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.

A new method of compensating for tissue-fraction and count-spillover effects, which require tissue segmentation only within a small volume surrounding the primary lesion of interest, was evaluated for SPECT imaging. Tissue-activity concentration estimates are obtained by fitting the measured projection data to a statistical model of the segmented tissue projections. Multiple realizations of two simulated human-torso phantoms, each containing 20 spherical 'tumours', 1.6 cm in diameter, with tumour-to-background ratios of 8:1 and 4:1, were simulated. Estimates of tumour- and background-activity concentration values for homogeneous as well as inhomogeneous tissue activities were compared to the standard uptake value (SUV) metrics on the basis of accuracy and precision. For perfectly registered, high-contrast, superficial lesions in a homogeneous background without scatter, the method yielded accurate (<0.4% bias) and precise (<6.1%) recovery of the simulated activity values, significantly outperforming the SUV metrics. Tissue inhomogeneities, greater tumour depth and lower contrast ratios degraded precision (up to 11.7%), but the estimates remained almost unbiased. The method was comparable in accuracy but more precise than a well-established matrix inversion approach, even when errors in tumour size and position were introduced to simulate moderate inaccuracies in segmentation and image registration. Photon scatter in the object did not significantly affect the accuracy or precision of the estimates.

We have developed a new 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 (99m)Tc concentration. All tumor activity estimates achieved bias after ∼ 15 ordered-subsets expectation maximization (OSEM) iterations (×10 subsets) , with better than 8% precision ( ≤ 25% greater than the Cramer-Rao lower bound). The projection-based fitting approach also outperformed three standardized uptake value (SUV)-like metrics, one of which was corrected for count spillover. In the bead phantom experiment, the mean ± standard deviation of the bias of VOI estimates of bead concentration were 0.9±9.5%, comparable to those of a perturbation geometric transfer matrix (pGTM) approach (-5.4±8.6%); however, VOI estimates were more stable with increasing iteration number than pGTM estimates, even in the presence of substantial axial misalignment between μCT and μSPECT image volumes.

Obtaining the best possible task performance using reconstructed SPECT images requires optimization of both the collimator and reconstruction parameters. The goal of this study is to determine how to perform this optimization, namely whether the collimator parameters can be optimized solely from projection data, or whether reconstruction parameters should also be considered. In order to answer this question, and to determine the optimal collimation, a digital phantom representing a human torso with 16 mm diameter hot lesions (activity ratio 8:1) was generated and used to simulate clinical SPECT studies with parallel-hole collimation. Two approaches to optimizing the SPECT system were then compared in a lesion quantification task: sequential optimization, where collimation was optimized on projection data using the Cramer–Rao bound, and joint optimization, which simultaneously optimized collimator and reconstruction parameters. For every condition, quantification performance in reconstructed images was evaluated using the root-mean-squared-error of 400 estimates of lesion activity. Compared to the joint-optimization approach, the sequential-optimization approach favoured a poorer resolution collimator, which, under some conditions, resulted in sub-optimal estimation performance. This implies that inclusion of the reconstruction parameters in the optimization procedure is important in obtaining the best possible task performance; in this study, this was achieved with a collimator resolution similar to that of a general-purpose (LEGP) collimator. This collimator was found to outperform the more commonly used high-resolution (LEHR) collimator, in agreement with other task-based studies, using both quantification and detection tasks.

Unlabelled: The aim of this work was to develop a rigorous evaluation methodology to assess performance of different acquisition and processing methods for variable patient sizes in the context of lesion detection in whole-body (18)F-FDG PET., Methods: Fifty-nine bed positions were acquired in 32 patients in 2-dimensional (2D) and 3-dimensional (3D) modes 1-4 h after (18)F-FDG injection (740 MBq) using a BGO PET scanner. Three spheres (1.0-, 1.3-, and 1.6-cm diameter) containing (68)Ge were also imaged separately in air, at locations corresponding to possible lesion sites in 2D and 3D (590 targets per condition). Each bed position was acquired for 7 min in 2D and 6 min in 3D and corrected for randoms using delayed window randoms subtraction (DWS) or randoms variance reduction (RVR). Sphere sinograms were attenuated using the 2D or 3D attenuation map derived from the transmission scan of the patient, after scaling 2D and 3D sinograms with identical factors to ensure marginal detectability. Resulting 2D sinograms were reconstructed with filtered backprojection (FBP) and ordered-subsets expectation maximization (OSEM) without any scatter or attenuation correction (FBP-NATS and OSEM-NATS) or corrected for scatter and attenuation and reconstructed using FBP (FBP-ATT) or attenuation-weighted OSEM (AWOSEM). 3D sinograms were processed identically after Fourier rebinning. Next, reconstructed volumes were compared on the basis of performance of a 3-channel Hotelling observer (CHO-SNR [SNR is signal-to-noise ratio]) in detecting the presence of a sphere of unknown size on an anatomic background while modeling observer noise. The noise equivalent count (NEC) rate was computed in 2D and 3D for 3 different phantoms sizes (40, 60, and 95 kg) and compared with lesion detection SNR., Results: 3D imaging yielded better lesion detectability than 2D (P < 0.025, 2-tailed paired t test) in patients of normal size (body mass index [BMI] < or = 31). However, 2D imaging yielded better lesion detectability than 3D in large patients (BMI > 31), as 3D performance deteriorated in large patients (P < 0.05). 2D and 3D yielded similar results for different lesion sizes. CHO-SNR were 40% greater for AWOSEM, FBP-ATT, and FBPNAT than for OSEM (P < 0.05), and AWOSEM yielded significantly better lesion detectability than did FBP. In all patients, RVR yielded a systematic improvement in CHO-SNR over DWS in both 2D and 3D. radicalNEC was characterized by a behavior similar to that of SNR(CHO) for the 3 different phantom sizes considered in this study.

Objective: We report results from a pilot study aimed at optimizing the use of CT bidimensional measurements and 18F-FDG PET maximum standardized uptake values (SUVs-(max)) for determining response to prolonged imatinib mesylate treatment in patients with advanced gastrointestinal stromal tumors (GISTs)., Subjects and Methods: Sixty-three patients enrolled in a multicenter trial evaluating imatinib mesylate therapy for advanced GIST underwent FDG PET at baseline and 1 month after initiation of treatment. Of these 63 patients, 58 underwent concomitant CT. Time-to-treatment failure (TTF) was used as the outcome measure. Patients were followed up over a range of 23.7 to 37 months (median, 31.7 months). The predictive power of change in CT bidimensional measurements, change in PET SUVmax, and PET SUVmax at 1 month after initiation of treatment were determined, optimized, and compared. The effectiveness of combining metrics was also evaluated., Results: Both a threshold PET SUVmax value of 2.5 at 1 month (p = 0.04) and the European Organization for Research and Treatment of Cancer (EORTC) criteria for partial response on FDG PET (25% reduction in PET SUVmax) at 1 month (p = 0.004) were predictive of prolonged treatment success. The Southwest Oncology Group (SWOG) criteria for partial response ((3) 50% reduction in CT bidimensional measurements) at 1 month were not predictive (p = 0.55) of TTF. Optimizing metrics improved results performance. An optimized PET SUVmax threshold of 3.4 (p = 0.00002), a reduction in the SUVmax of 40% (p = 0.002), and an optimized CT bidimensional measurement threshold--that is, no growth from baseline to 1 month (p = 0.00005)--outperformed the existing standards (i.e., EORTC and SWOG criteria). Combinations of metrics did not improve performance., Conclusion: The two best metrics were the optimized PET SUVmax threshold of 3.4 at 1 month (p = 0.00002) and the optimized CT bidimensional measurement threshold (no growth from baseline to 1 month, p = 0.00005) in this patient group.

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 scanner using both new and standard collimators. The new variable focusing collimator SensOgrade 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 cm3 in volume. 99mTc 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 99mTc-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 location 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 99mTc-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.

Purpose: The purpose of this study was to investigate the feasibility and utility of dual-isotope SPECT for differential diagnosis of idiopathic Parkinson's disease (IPD) and multiple system atrophy (MSA)., Methods: Simultaneous (99m)Tc-ECD/123I-FP-CIT studies were performed in nine normal controls, five IPD patients, and five MSA patients. Projections were corrected for scatter, cross-talk, and high-energy penetration, and iteratively reconstructed while correcting for patient-specific attenuation and variable collimator response. Perfusion and dopamine transporter (DAT) function were assessed using voxel-based statistical parametric mapping (SPM2) and volume of interest quantitation. DAT binding potential (BP) and asymmetry index (AI) were estimated in the putamen and caudate nucleus., Results: Striatal BP was lower in IPD (55%) and MSA (23%) compared to normal controls (p<0.01) , and in IPD compared to MSA (p<0.05). AI was greater for IPD than for MSA and controls in both the caudate nucleus and the putamen (p<0.05). There was significantly decreased perfusion in the left and right nucleus lentiformis in MSA compared to IPD and controls (p<0.05)., Conclusion: Dual-isotope studies are both feasible in and promising for the diagnosis of parkinsonian syndromes.

Maximum-likelihood (ML) estimation is an established paradigm for the assessment of imaging system performance in nonlinear quantitation tasks. At high signal-to-noise ratio (SNR), ML estimates are asymptotically Gaussian-distributed, unbiased and efficient, thereby attaining the Cramer-Rao bound (CRB). Therefore, at high SNR the CRB is useful as a predictor of the variance of ML estimates and, consequently, as a basis for measures of estimation performance. At low SNR, however, the achievable parameter variances are often substantially larger than the CRB and the estimates are no longer Gaussian-distributed. These departures imply that inference about the estimates that is based on the CRB and the assumption of a normal distribution will not be valid. We have found previously that for some tasks these effects arise at noise levels considered clinically acceptable. We have derived the mathematical relationship between a new measure, chi2(pdf-ML), and the expected probability density of the ML estimates, and have justified the use of chi2(pdf-ML)-isocontours in parameter space to describe the ML estimates. We validated this approach by simulation experiments using spherical objects imaged with a Gaussian point spread function. The parameters, activity concentration and size, were estimated simultaneously by ML, and variances and covariances calculated over 1000 replications per condition from 3D image volumes and from 2D tomographic projections of the same object. At low SNR, where the CRB is no longer achievable, chi2(pdf-ML)-isocontours provide a robust prediction of the distribution of the ML estimates. At high SNR, the chi2(pdf-ML)-isocontours asymptotically approach the analogous chi2(pdf-F)-contours derived from the Fisher information matrix. The chi2(pdf-ML) model appears to be suitable for characterization of the influence of the noise level and characteristics, the task, and the object on the shape of the probability density of the ML estimates at low SNR. Furthermore, it provides unique insights into the causes of the variability of estimation performance.

Unlabelled: We have addressed 2 major challenges of (82)Rb cardiac PET, noninvasive estimation of an accurate input function and absolute quantitation of myocardial perfusion, using a generalized form of least-squares factor analysis of dynamic sequences (GFADS) and a novel compartment analysis approach., Methods: Left and right ventricular (LV + RV) time-activity curves (TACs) were generated from 10 rest/stress studies, and 30 myocardial TACs were modeled to cover a range of clinical values. Two-dimensional PET Monte Carlo simulations of the LV, RV, myocardium, and other organs were generated separately and combined using the above TACs to form 30 realistic dynamic (82)Rb studies. LV and RV TACs were estimated by GFADS and used as input to a 2-compartment kinetic analysis that estimates parametric maps of myocardial tissue extraction (k(1)) and egress (k(2)), as well as LV + RV contributions (f(v), r(v)), by orthogonal voxel grouping. In addition, 13 patients were injected with 2.22 +/- 0.19 GBq (60 +/- 5 mCi) of (82)Rb and imaged dynamically for 6 min at rest and during dipyridamole stress., Results: In Monte Carlo simulations, GFADS yielded estimates of the 3 factors and corresponding factor images, with average errors of -4.2% +/- 6.3%, 3.5% +/- 4.3%, and 2.0% +/- 5.5% in the LV, RV, and myocardial factor estimates, respectively. The estimates were significantly more accurate and robust to noise than those obtained using TACs based on manually drawn volumes of interest (P < 0.01). The 2-compartment approach yielded accurate k(1), k(2), f(v), and r(v) parametric maps; the average error of estimates of k(1) was 6.8% +/- 3.6%. In all patient studies, our approach yielded robust estimates of k(1), k(2), f(v), and r(v), which correlated very well with the status of the subject and the catheterization results., Conclusion: Quantitative dynamic (82)Rb PET using generalized factor analysis of dynamic sequences and compartmental modeling yields estimates of parameters of absolute myocardial perfusion and kinetics with errors of <9%.

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., (© 2005 American Association of Physicists in Medicine.)

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.

Unlabelled: We investigated the impact of the quantitation and reconstruction protocol on clinical tasks. The performance of standard clinical reconstruction procedures in discrimination tasks related to the diagnosis of prodromal Alzheimer's disease (AD) was compared with the performance of a quantitative approach incorporating improved corrections for scatter, attenuation, intrinsic spatial resolution, and distance-dependent spatial resolution., Methods: Seventeen normal controls (normal group), 56 subjects who did not have dementia, who did have memory problems, but who did not develop AD within 5 y of follow-up (questionable group), and 27 subjects who did not have dementia, who did have memory problems, and who did develop AD over the follow-up period (converter group) were considered in this study. (99m)Tc-hexamethylpropyleneamine oxime SPECT and MRI studies were performed for each subject at baseline. The standard quantitation protocol (STD), routinely used in our clinic, consisted of Compton window scatter correction followed by filtered backprojection with attenuation correction using a uniform attenuation map. In the improved quantitative approach (QUAN), projections were corrected for scatter by use of a general spectral method and reconstructed by use of ordered-subset(s) expectation maximization, incorporating corrections for collimator response and attenuation using both a uniform attenuation map (QUANunif) and a nonuniform attenuation map (QUANnonunif). Mean SPECT activity concentration and MRI volume were estimated for 7 structures: rostral anterior cingulate gyrus, caudal anterior cingulate gyrus, posterior cingulate gyrus, hippocampus, basal forebrain, amygdala, and the banks of the superior temporal sulcus. Data were analyzed by pairwise discriminant analysis, and performance in binary group discrimination was measured by correlated receiver-operating-characteristic analysis., Results: The use of QUANnonunif yielded a small but systematic improvement in discrimination accuracy for normal versus converter groups (accuracy or area under the receiver-operating-characteristic curve [Az], 0.965), normal versus questionable groups (Az, 0.973), and questionable versus converter groups (Az, 0.881) compared with the results obtained with QUANunif (Az, 0.955, 0.962, and 0.866, respectively). Discrimination performance was significantly lower (P < 0.05) with STD than with QUAN in all 3 tasks (Az with STD, 0.906, 0.878, and 0.768, respectively). MRI volume estimation led to a lower overall performance in all 3 tasks than did QUANnonunif (Az with MRI, 0.947, 0.917, and 0.872, respectively)., Conclusion: Improved quantitative image reconstruction with accurate compensation for scatter, attenuation, and variable collimator response led to significantly better performance in discrimination tasks related to the diagnosis of prodromal AD than did standard clinical reconstruction procedures. The use of a nonuniform brain attenuation map yields a small improvement in discrimination accuracy.

Objective: To identify group differences in the prodromal phase of Alzheimer disease (AD) using quantitative single-photon emission computed tomography (SPECT) perfusion and magnetic resonance imaging (MRI) volume measures within specific volumes of interest., Setting: Gerontology research unit., Participants: There were 17 healthy controls, 56 nondemented patients with memory problems who did not develop AD during 3 to 5 years of follow-up (questionables), and 27 nondemented patients with memory problems who developed AD during follow-up (converters)., Methods: A Tc 99m hexamethylpropyleneamine oxime SPECT study and an MRI were performed in each participant at baseline. Mean SPECT activity concentration and MRI volume were estimated within 9 structures: rostral anterior cingulate, caudal anterior cingulate, posterior cingulate, hippocampus, entorhinal cortex, basal forebrain, temporal horn, amygdala, and the banks of the superior temporal sulcus. Data were analyzed using overall and pairwise discriminant analysis, and performance in pairwise group discrimination was measured using correlated receiver operating characteristic curve analysis., Results: The overall (3-group) discriminant function was significant for SPECT (F test, P<.001) and MRI (F test, P<.0001). For the SPECT analysis, the ranking of structures for discriminating among the 3 groups was, in order of decreasing discriminating power, caudal anterior cingulate, temporal horn, superior temporal sulcus, entorhinal cortex, hippocampus, rostral anterior cingulate, amygdala, basal forebrain, and posterior cingulate. For the MRI analysis, this ranking was entorhinal cortex, superior temporal sulcus, temporal horn, hippocampus, amygdala, caudal anterior cingulate, rostral anterior cingulate, basal forebrain, and posterior cingulate. Combining the 2 modalities yielded significantly better discrimination performance than did either alone. Furthermore, the correlation between SPECT and MRI measures was low., Conclusion: Measures of structure activity concentration and volume carry independent information; both reveal group differences in prodromal AD.

Unlabelled: We have compared the use of two (93 and 185 keV) and three (93, 185, and 300 keV) photopeaks for Ga-67 tumor imaging and optimized the placement of each energy window., Methods: The bases for optimization and evaluation were ideal and Bayesian signal-to-noise ratios (SNR) for the detection of spheres embedded in a realistic anthropomorphic digital torso phantom and ideal SNR for the estimation of their size and activity concentration. Seven spheres of radii ranging from 1 to 3 cm, located at several sites in the torso, were simulated using a realistic Monte Carlo program. We also calculated the ideal SNR for the detection from simple phantom acquisitions., Results: For detection and estimation tasks, the optimum windows were identical for all sphere sizes and locations. For the 93 keV photopeak, the optimal window was 84-102 keV for the detection and 87-102 keV for estimation; these windows are narrower than the 20% window often used in the clinic (83-101 keV). For the 185 keV photopeak, the optimal window was 170-220 keV for the detection and 170-215 keV for estimation; these are substantially different than the 15% window used in our clinic (171-199 keV). For the 300 keV photopeak, the optimal window for detection was 270-320 keV, and for estimation, 280-320 keV. Using the three optimized, rather than only the two lower-energy, windows yielded a 9% increase in the SNR for the detection of the 3 cm diam sphere (a 12% increase for a 2 cm diam sphere) and a 7% increase in the SNR for estimation of its size. For the acquired phantom data, detection also increased by 9%-12% when using three, rather than two, energy windows.

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.

Unlabelled: Dual-isotope imaging can allow simultaneous assessment of brain perfusion using a 99mTc-labeled tracer and neurotransmission using an 123I-labeled tracer. However, the images are affected by scatter, cross talk, attenuation, distance-dependent collimator response (DCR), and partial-volume effect. We determined the accuracy and precision of activity quantitation in simulated normal and pathologic studies of simultaneous 123I/99mTc brain SPECT when compensating for all degrading phenomena., Methods: Monte Carlo simulations were performed using the Zubal brain phantom. Contamination caused by high-energy 123I decay photons was incorporated. Twenty-four 99mTc and 123I activity distributions were simulated on the basis of normal and pathologic patient activity distributions. Cross talk and scatter were corrected using a new method based on a multilayer perceptron artificial neural network (ANN), as well as by the asymmetric window (AW) approach; for comparison, unscattered (U) photons of 99mTc and 123I were recorded. Nonuniform attenuation and DCR were modeled in an iterative ordered-subset expectation maximization (OSEM) algorithm. Mean percentage biases and SDs over the 12 normal and 12 pathologic simulated studies were computed for each structure with respect to the known activity distributions., Results: For 123I, AW + OSEM yielded a bias of 7% in the cerebellum, 21% in the frontal cortex, and 36% in the corpus callosum in the simulated normal population. The bias was increased significantly in the striata of simulated pathologic studies (P < 0.05). The bias associated with ANN was significantly lower (<9% in these brain structures, P < 0.05). For 99mTc with AW + OSEM, the bias was 60% in the corpus callosum, 36% in the striata, and 18%-22% in the cortical lobes in the simulated normal population. This bias was <11% in all brain structures with ANN. In the simulated pathologic population, the bias associated with AW increased significantly in the cortical lobes to 55% (P < 0.05), although it did not change significantly with ANN., Conclusion: The accuracy and variability over simulated normal and pathologic studies of both 99mTc and 123I activity estimates were very close with ANN to those obtained with U + OSEM. ANN + OSEM is a promising approach for absolute activity quantitation in simultaneous 99mTc/123I SPECT.