The use of a novel method for SPECT/CT quantification of 99m-Tc-PYP uptake in the evaluation of ATTR cardiac amyloidosis

Funding Acknowledgements Type of funding sources: None. Background/Introduction: Bone scintigraphy with 99m-Technecium-Pyrophosphate (99m-Tc-PYP) with planar and SPECT imaging is now commonplace for the non-invasive diagnosis of ATTR cardiac amyloidosis. However, the quantification of 99m-Tc-PYP uptake is based on a semi-quantitative visual score and a heart to contralateral lung ratio which suffer from poor reproducibility. A more robust method of quantifying uptake and reporting results would be beneficial and may be possible using volumetric assessment with fused SPECT/CT acquisition. Purpose The aim of this study was to evaluate the performance of a novel semi-automated quantitative software to diagnose ATTR cardiac amyloidosis in patients with a clinical suspicion of cardiac amyloidosis who underwent 99m-Tc-PYP SPECT/CT imaging. Methods This was a retrospective, single-center study of consecutive patients who underwent 99m-Tc-PYP SPECT/CT imaging from September to December 2020. Quantification software was used to obtain standardized uptake values (SUVs) of 99m-Tc-PYP activity in the whole heart using SPECT/CT data. The total SUVs, mean SUVs, and percentage of injected tracer dose in the heart, as well as two other sets of these measurements adjusted for residual blood pool activity were obtained. Activity in the lung and bone was used to calculate heart to bone and heart to right lung ratios. The results from the software quantification were compared to the results from planar imaging as well as to the final clinical diagnosis of amyloidosis. Results A total of 59 patients were imaged during this time with an average age of 74.1 ± 11.8, and 32 (54.2%) were male. After excluding 8 patients for technical issues, 12 patients were found to be positive for amyloid, 39 were negative, and the average imaging delay time was 75.0 ± 15.2 minutes. 13 methods of assessment were evaluated with the metric of the percentage of injected tracer dose found in the heart that was adjusted for the mean residual blood pool activity having the best discrimination between abnormal and normal studies. The mean percentage of injected dose in positive patients was 2.87% vs 0.98% in the patients without amyloidosis (p < 0.0001). Using a cutoff of 2% to ensure that no patients with amyloid would be missed by screening, there was 100% sensitivity, 94.9% specificity, and 96.1% accuracy. There was a significant difference in the percentage injected dose based on gradations of planar heart to contralateral lung ratio and planar visual score. Conclusion Volumetric software quantification may be a superior method of evaluating 99m-Tc-PYP cardiac amyloidosis studies. This methodology may allow for a quantitative definition of a normal or abnormal 99m-Tc-PYP cardiac amyloid study and provide for the potential of following response to therapy.

Positron Emission Tomography Imaging Reveals an Importance of Saturable Liver Uptake Transport for the Pharmacokinetics of Metoclopramide

Positron emission tomography (PET) imaging using [11C]metoclopramide, a P-glycoprotein (P-gp) substrate, was used to investigate the contribution of transport processes to metoclopramide liver clearance. The liver kinetics obtained after injection of [11C]metoclopramide were measured using PET in rats (n=4‐5) in the absence (tracer dose) and the presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using i.v. tariquidar (8 mg/kg). Corresponding [11C]metoclopramide kinetics and metabolism in plasma (n=3) were measured using radio-HPLC analysis. [11C]metoclopramide exposure to the liver and plasma was described by the area under the time-activity curve (AUC) of the radioactivity kinetics in the liver and parent [11C]metoclopramide kinetics in plasma, respectively. The pharmacologic dose of metoclopramide resulted in a ∼2.2-fold increase in [11C]metoclopramide AUCplasma, while P-gp inhibition did not. AUCliver was lower using the pharmacologic dose (42.9 ± 13.8 SUV·min) compared with the tracer dose (210.0 ± 32.4 SUV·min). P-gp inhibition enhanced the liver exposure in the pharmacologic condition only (81.0 ± 3.1 SUV·min). [11C]metoclopramide PET imaging suggests an unpredicted role for hepatocyte uptake transporter(s) in controlling metoclopramide pharmacokinetics in addition to the known contribution of the metabolic enzymes and the P-gp.

Total-body creatine pool size and skeletal muscle mass determination by creatine-(methyl-d3) dilution in rats

There is currently no direct, facile method to determine total-body skeletal muscle mass for the diagnosis and treatment of skeletal muscle wasting conditions such as sarcopenia, cachexia, and disuse. We tested in rats the hypothesis that the enrichment of creatinine-( methyl-d3) (D3-creatinine) in urine after a defined oral tracer dose of D3-creatine can be used to determine creatine pool size and skeletal muscle mass. We determined 1) an oral tracer dose of D3-creatine that was completely bioavailable with minimal urinary spillage and sufficient enrichment in the body creatine pool for detection of D3-creatine in muscle and D3-creatinine in urine, and 2) the time to isotopic steady state. We used cross-sectional studies to compare total creatine pool size determined by the D3-creatine dilution method to lean body mass determined by independent methods. The tracer dose of D3-creatine (<1 mg/rat) was >99% bioavailable with 0.2–1.2% urinary spillage. Isotopic steady state was achieved within 24–48 h. Creatine pool size calculated from urinary D3-creatinine enrichment at 72 h significantly increased with muscle accrual in rat growth, significantly decreased with dexamethasone-induced skeletal muscle atrophy, was correlated with lean body mass ( r = 0.9590; P < 0.0001), and corresponded to predicted total muscle mass. Total-body creatine pool size and skeletal muscle mass can thus be accurately and precisely determined by an orally delivered dose of D3-creatine followed by the measurement of D3-creatinine enrichment in a single urine sample and is promising as a noninvasive tool for the clinical determination of skeletal muscle mass.