Automated Reference Region Extraction and Population-Based Input Function for Brain [¹¹C]TMSX PET Image Analyses

Abstract

[ 11 C]TMSX ([7-N-methyl-11 C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) is a selective adenosine A2A receptor (A 2A R) radioligand. In the central nervous system (CNS), A 2A R are linked to dopamine D 2 receptor function in striatum, but they are also important modulators of inflammation. The golden standard for kinetic modeling of brain [ 11 C]TMSX positron emission tomography (PET) is to obtain arterial input function via arterial blood sampling. However, this method is laborious, prone to errors and unpleasant for study subjects. The aim of this work was to evaluate alternative input function acquisition methods for brain [ 11 C] TMSX PET imaging. First, a noninvasive, automated method for the extraction of gray matter reference region using supervised clustering (SCgm) was developed. Second, a method for obtaining a population-based arterial input function (PBIF) was implemented. These methods were created using data from 28 study subjects (7 healthy controls, 12 multiple sclerosis patients, and 9 patients with Parkinson's disease). The results with PBIF correlated well with original plasma input, and the SCgm yielded similar results compared with cerebellum as a reference region. The clustering method for extracting reference region and the population-based approach for acquiring input for dynamic [ 11 C]TMSX brain PET image analyses appear to be feasible and robust methods, that can be applied in patients with CNS pathology.

Reliable quantification of 18F-GE-180 PET neuroinflammation studies using an individually scaled population-based input function or late tissue-to-blood ratio

“…This is analogous to PET with [ 18 F]fluorodeoxyglucose (FDG), where the (scan-time corrected) late lesion-to-blood uptake ratio shows excellent correlation with the FDG metabolic rate constant estimated by graphical analysis, better than the widely used standard uptake value (SUV) [36,37]. The performance of population-based input functions might be improved by using two or more blood samples for individual scaling of the input function template [31,33,34,46]. However, regional V T estimates obtained with the population-based method PB1 using a single blood sample at 27.5 min were strongly correlated with the regional reference V T in this study (mean Pearson coefficient over all ROIs = 0.989 ± 0.006, range 0.971-0.992; all p < 10 −10 ).…”

“…Some previous studies employed the same scaling method for the generation of the input function template from "old" subjects (with full blood sampling) as for the generation of individual population-based input functions from the input function template for "new" subjects [31,32,35]. In the present study, two different scaling methods were used.…”

“…Population-based input functions for tracer kinetic modeling have been successfully used for quantitative analysis of brain PET with FDG [26][27][28][29] and a variety of other tracers [30][31][32][33][34][35]. The aim of the present study was to evaluate methods for quantitative analysis of 18 F-GE-180 PET using populationbased blood curves that either require only a single late blood sample or no blood at all.…”

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

“…Yes (Zhou et al 2017a(Zhou et al , 2017b(Zhou et al , 2017c(Zhou et al , 2017dSakata et al 2017;Ishibashi et al 2018;Zhou et al 2014) A2aR [ (Rissanen et al 2013;Mishina et al 2007Mishina et al , 2011Naganawa et al 2007Naganawa et al , 2014Lahesmaa et al 2018;Rissanen et al 2015) Preclinically used B16-F10 tumors, to detect PD-1 expressing tumor infiltrating lymphocytes (TILs) (Natarajan et al 2015). PET images obtained at 1-48 h after injection indicated tracer uptake mainly in the tumor and spleen, which was both found to be PD-1 specific T cell-mediated uptake confirmed by bioluminescence, IHC, and concurrent blocking of uptake by co-injection of an excess unlabeled tracer.…”

Potential Therapeutic Applications of Adenosine A2A Receptor Ligands and Opportunities for A2A Receptor Imaging

“…Various techniques were tested to acquire an input function (arterial blood sampling with metabolite correction, a population‐based arterial input function, and a non‐invasive approach to extract reference voxels using supervised cluster analysis). The distribution volume of [ 11 C]TMSX in normal‐appearing white matter of the patients was significantly (+22%) increased in comparison to the value observed in healthy controls and this increase was associated with higher scores on the expanded disability status scale . The results of these studies were interpreted as evidence for increases of A 2A R density in white matter of MS patients, related to inflammatory processes.…”