Parametric Mapping for TSPO PET Imaging with Spectral Analysis Impulsive Response Function

Abstract

Purpose: The aim of this study was to investigate the use of spectral analysis (SA) for voxel-wise analysis of TSPO PET imaging studies. TSPO PET quantification is methodologically complicated by the heterogeneity of TSPO expression and its cell-dependent modulation during neuroinflammatory response. Compartmental models to account for this complexity exist, but they are unreliable at the high noise typical of voxel data. On the contrary, SA is noise-robust for parametric mapping and provides useful information about tracer kinetics with a free compartmental structure.

Procedures: SA impulse response function (IRF) calculated at 90 min after tracer injection was used as main parameter of interest in 3 independent PET imaging studies to investigate its sensitivity to (1) a TSPO genetic polymorphism (rs6971) known to affect tracer binding in a cross-sectional analysis of healthy controls scanned with [11C]PBR28 PET; (2) TSPO density with [11C]PBR28 in a competitive blocking study with a TSPO blocker, XBD173; and (3) the higher affinity of a second radiotracer for TSPO, by using data from a head-to-head comparison between [11C]PBR28 and [11C]ER176 scans.

Results: SA-IRF produced parametric maps of visually good quality. These were sensitive to TSPO genotype (mean relative difference between high- and mixed-affinity binders = 25 %) and TSPO availability (mean signal displacement after 90 mg oral administration of XBD173 = 39 %). Regional averages of voxel-wise IRF estimates were strongly associated with regional total distribution volume (V_T) estimated with a 2-tissue compartmental model with vascular compartment (Pearson's r = 0.86 ± 0.11) but less strongly with standard 2TCM-V_T (Pearson's r = 0.76 ± 0.32). Finally, SA-IRF estimates for [11C]ER176 were significantly higher than [11C]PBR28 ones, consistent with the higher amount of specific binding of the former tracer.

Conclusions: SA-IRF can be used for voxel-wise quantification of TSPO PET data because it generates high-quality parametric maps, it is sensitive to TSPO availability and genotype, and it accounts for the complexity of TSPO tracer kinetics with no additional assumptions.

Keywords: PET; Parametric mapping; Spectral analysis; TSPO.

Fig. 1.

SA kinetic spectrum and impulsive response function. a Representative kinetic spectrum for a healthy subject, which revealed 4 different components: a trapping for β = 0 (blue), a slow component for β = 0.053 min⁻¹(green), a fast component for β = 0.300 min⁻¹ (red), and high frequency component for β = 5 min⁻¹(cyan) likely to be associated to fractional blood volume. b Associated impulse response function (IRF) for tracer activity (black line) which was measured by the sum of three individual tissue components of the spectrum (blue, green, and red curves, respectively).

Fig. 2.

SA-IRF parametric mapping and TSPO genetic polymorphism. a, b SA-IRF (1/min). c, d SA V_T (ml/cm³). e, f SA blood volume fraction (unitless). g, h Number of components. The images show a representative HAB (top row) and MAB (bottom row) subject from a [11C]PBR28 PET imaging study. No visualisation filter is applied.

Fig. 3.

SA-IRF parametric mapping and TSPO blocking. a, b SA-IRF (1/min). c, d SA blood volume fraction (unitless). e, f Number of components. The images show a representative subject from a [11C]PBR28 PET imaging study before (top row) and after (bottom row) XBD173 blocking. No visualisation filter is applied.

Fig. 4

SA-IRF parametric mapping and TSPO tracer affinity. Head-to-head comparison of a [11C]PBR28 PET scan (a) and [11C]ER176 PET scan (b) for a representative healthy subject. No visualisation filter is applied. c Distribution of spectral components across the brain for the two radiotracers.