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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.)

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.)

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.

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.

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.

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.