Quantitative in vivo imaging of microglia activation using [11C]PK11195 and two reference tissue models

Poster Presentations / NeuroImage 31 (2006) T44 – T186

T79

Poster Presentation No.: 034

Quantitative in vivo imaging of microglia activation using [11C]PK11195 and two reference tissue models Alessandra Bertoldo,1 L. Pietra,2,3,4 R.M. Moresco,2,3,4 A. Panzacchi,2,3,4 M.C. Gilardi,2,3,4 M. Matarrese,2,3,4 E. Turolla,2,3,4 F. Fazio,2,3,4 C. Cobelli1 1

University of Padova, Padova, Italy 2 IBFM-CNR, Milan, Italy 3 San Raffaele Scientific Institute, Milan, Italy 4 University of Milan-Bicocca, Milan, Italy

Introduction: [11C]PK11195 is a selective peripheral benzodiazepine receptor (PBR) antagonist that allows in vivo study of activated microglia. Currently, the simplified reference tissue model (SRTM; Lammerstma and Hume, Neuroimage 1996) is the most used approach and has recently been shown to perform best when neither arterial plasma nor metabolites activity is measured (1). However, SRTM BP values have been shown to be much lower than those obtained by using a plasma input model (2). SRTM can be improved by accounting for cerebral blood volumes presence both in reference and target tissues (SRTM_Vb; Gunn et al., Neuroimage, 1998, 8:426 – 440). Here, we investigated the performance of STRM against SRTM_Vb for the analysis of [11C]PK11195 images. Materials and methods: PET studies were performed in four healthy subjects with an 18-ring tomograph (GE Advance; General Electric Medical System, Milwaukee, WI, USA). Immediately after tracer injection, 35 sequential scans over 60 min were simultaneously acquired in 3D mode. No arterial plasma time activity nor metabolites were sampled. The reference region activity (Cref) was extracted by using hierarchical clustering and employed as input function to SRTM in order to estimate RI (ratio of tissue compared to that in the reference region delivery), k2 (efflux rate constant from tissue), and BP (binding potential) values. An algorithm based on hierarchical clustering was also used to extract the whole blood tracer activity (Cb) directly from the images. Cref and Cb were used as input functions to SRTM_Vb, the blood volume in the reference region was fixed to 5%, and RI, k2, BP and Vb (blood volume in tissue) were estimated. Both STRM and SRTM_Vb were applied at pixel level. Results: BP estimates obtained with SRTM and SRTM_Vb are shown in Table 1. SRTM_Vb increases BP estimates with respect to SRTM by 1.45-fold, at minimum, in pons and thalamus and by 3.47-fold, at maximum, in frontal cortex (mean-fold increase: 2.5 T 0.08). Average Vb values derived using SRTM_Vb are 7 T 1%, virtually identical to those obtained by using arterial input function modeling (3). Conclusion: These preliminary results show that SRTM_Vb increases BP with respect to SRTM which is known to underestimate BP in comparison with arterial input function modeling (4). Further investigations are needed to assess the effect of blood volume correction in SRTM model in humans affected by disease in which activated microglia may contribute to tissue destruction and disease progression. Also the impact, on parameter estimation, of partial volume presence in the whole blood activity curve derived from the images deserves more studies.

Table 1 SRTM and SRTMvb estimates of BP BP T SD SRTM SRTM Vb

Cerebellum

Pons

Frontal cortex

Thalamus

Basal ganglia

Occipital cortex

0.19 T 0.12 0.48 T 0.07

0.48 T 0.08 0.70 T 0.21

0.11 T 0.06 0.39 T 0.09

0.37 T 0.07 0.53 T 0.06

0.12 T 0.09 0.38 T 0.11

0.15 T 0.08 0.47 T 0.22

References: Kropholler et al., 2005. J Cereb Blood Flow Metab 25, 842 – 51. Kropholler et al., 2006. J Cereb Blood Flow Metab (advance online publication). doi:10.1016/j.neuroimage.2006.04.068