Pseudoreference Regions for Glial Imaging with 11C-PBR28: Investigation in 2 Clinical Cohorts

Abstract

The translocator protein (TSPO) is a commonly used imaging target to investigate neuroinflammation. Although TSPO imaging demonstrates great promise, its signal exhibits substantial interindividual variability, which needs to be accounted for to uncover group effects that are truly reflective of neuroimmune activation. Recent evidence suggests that relative metrics computed using pseudoreference approaches can minimize within-group variability and increase sensitivity to detect physiologically meaningful group differences. Here, we evaluated various ratio approaches for TSPO imaging and compared them with standard kinetic modeling techniques, analyzing 2 different disease cohorts. Patients with chronic low back pain (cLBP) or amyotrophic lateral sclerosis (ALS) and matching healthy controls received ¹¹C-PBR28 PET scans. The occipital cortex, cerebellum and whole brain were first evaluated as candidate pseudoreference regions by testing for the absence of group differences in SUV and distribution volume (V_T) estimated with an arterial input function. The SUV from target regions (cLBP study, thalamus; ALS study, precentral gyrus) was normalized with the SUV from candidate pseudoreference regions (i.e., occipital cortex, cerebellum, and whole brain) to obtain SUVR_occip, SUVR_cereb, and SUVR_WB The sensitivity to detect group differences in target regions was compared using various SUVR approaches, as well as distribution volume ratio (DVR) estimated with (blDVR) or without arterial input function (refDVR), and V_T Additional voxelwise SUVR group analyses were performed. We observed no significant group differences in pseudoreference V_T or SUV, excepting whole-brain V_T, which was higher in cLBP patients than controls. Target V_T elevations in patients (P = 0.028 and 0.051 in cLBP and ALS, respectively) were similarly detected by SUVR_occip and SUVR_WB, and by refDVR and blDVR (less reliably by SUVR_cereb). In voxelwise analyses, SUVR_occip, but not SUVR_cereb, identified regional group differences initially observed with SUVR_WB, and in additional areas suspected to be affected in the pathology examined. All ratio metrics were highly cross-correlated, but generally were not associated with V_T. Although important caveats need to be considered when using relative metrics, ratio analyses appear to be similarly sensitive to detect pathology-related group differences in ¹¹C-PBR28 signal as classic kinetic modeling techniques. The occipital cortex may be a suitable pseudoreference region, at least for the populations evaluated, pending further validation in larger cohorts.

Keywords: astrocytes; human; microglia; neuroimmunology; neuroinflammation.

FIGURE 1.

Group comparison of SUV (left) and V_T (right) from candidate pseudoreference regions evaluated in this work. Boxes represent 25%–75% interquartile range; horizontal line represents median. Diamonds represent subjects with the high-affinity TSPO genotype (Ala/Ala in the TSPO polymorphism); squares represent subjects with mixed-affinity genotype (Ala/Thr). CTRL = control.

FIGURE 2.

Group comparison of 0- to 90-min time–activity curves for candidate pseudoreference regions. Each data point represents average within-group SUV for that time point ± SD. In cLBP plots (left), both patients matching same control subject are included. CTRL = control.

FIGURE 3.

Group comparison of target V_T estimates for cLBP (top) and ALS (bottom) groups. CTRL = control.

FIGURE 4.

Group differences in target SUVR for each pseudoreference region. Horizontal bars represent group median. In cLBP plots (top), both patients matching same control subject are included as data points, but median value reflects only best matching patient included. CTRL = control.

FIGURE 5.

ROC curves of target SUVR (dashed lines) and V_T (solid line) for each pseudoreference region. Line of identity (chance, no discriminatory power) is shown in black.

FIGURE 6.

Regions of elevated ¹¹C-PBR28 SUVR in patients compared with controls. Results from SUVR_WB analyses (analyses from original studies) are shown in green colorscale; SUVR_occip results are shown in red-yellow colorscale. (Top) cLBP > controls. (Bottom) ALS > controls. No regions were significant in either cLBP < controls or ALS < controls contrasts. aMCC = anterior midcingulate cortex; CTRL = control; dmPFC = dorsomedial prefrontal cortex; PCC = posterior cingulate cortex; SCA = subcallosal area; SMA = supplementary motor area; Thal = thalamus; vmPFC = ventromedial prefrontal cortex.

FIGURE 7.

Group comparison of refDVR_occip and blDVR_occip. Horizontal bars represent group median. CTRL = control.