¹¹C-PBR28 and ¹⁸F-PBR111 Detect White Matter Inflammatory Heterogeneity in Multiple Sclerosis

Abstract

The objective of this study was to assess microglial activation in lesions and in normal-appearing white matter (NAWM) of multiple sclerosis (MS) patients using PET. Thirty-four MS patients (7 with secondary progressive MS [SPMS], 27 with relapsing remitting MS [RRMS]) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO) binding status, underwent PET scanning with TSPO radioligands (C-PBR28 or F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudoreference region). White matter lesions (WMLs) were classified as "active" (DVR highest in the lesion), "peripherally active" (perilesional DVR highest), "inactive" (DVR highest in surrounding NAWM), or "undifferentiated" (similar DVR across lesion, perilesional and NAWM volumes). The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, = 4 × 10). A higher proportion of lesions were inactive in patients with SPMS (35%) than RRMS (23%), but active lesions were found in all patients, including those on highly efficacious treatments. TSPO radioligand uptake was increased in the brains of MS patients relative to healthy controls with 2 TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. Their independent prognostic significance needs further investigation.

Confirmation of Specific Binding of the 18-kDa Translocator Protein (TSPO) Radioligand [18F]GE-180: a Blocking Study Using XBD173 in Multiple Sclerosis Normal Appearing White and Grey Matter

“…[ 11 C]PBR28 has been validated with blocking experiments prior to our study, both in healthy controls [6,26] and in a disease cohort [27]. [ 11 C]PBR28 is generally accepted as an effective TSPO tracer in vivo [28][29][30][31][32] although exhibits counterintuitively decreased V T in subjects with neuroinflammation [29]. In Owen et al [6], the V ND of [ 11 C]PBR28 was 1.98 ml/cm 3 (~50 % of V T ), while Fujita et al [26] reported an average V T of 4.3 ml/cm 3 (in HABs) and a BP ND of 1.2, giving a very similar V ND of 1.98 ml/cm 3 (~45 % of V T ).…”

“…Participants had radial artery cannulation and blood was withdrawn continuously at a target rate of 2.5 ml min −1 from the start of each scan for the first 15 min. In addition, discrete blood samples were drawn at 0, 5, 10, 15, 30, 50, 70 and 90 min ([ 18 F]GE-180) or 0, 5,10,15,20,25,30,40,50,60,70,80 and 90 min ([ 11 C]PBR28) for metabolite analysis. For [ 18 F]GE-180, tracer concentrations in whole blood and plasma were measured in a well counter and radiometabolite analysis performed using two high performance liquid chromatography (HPLC) systems (Agilent 1260 Infinity and Agilent 110 Series) in isocratic mode.…”

Exploring the heterogeneity of MS lesions using positron emission tomography: a reappraisal of their contribution to disability

“…First, the affinity to platelets, monocytes and plasma proteins alters the free plasma concentration of the tracers across subjects, with a possible impact on input function calculation, when input function is used for signal modeling . This evidence supports the application of quantification methods based on the extraction of reference regions directly from brain images in order to avoid fluctuation in the measure of input function, a strategy that was applied for PBR28 and [ 18 F]DPA‐714 . Second, a blood brain barrier (BBB) signal from endothelial TSPO, in particular for high affinity TSPO tracers may also interfere with the signal quantification from brain tissues .…”

Gliosis and Neurodegenerative Diseases: The Role of PET and MR Imaging

“…Although the findings of an increased uptake of this tracer in these pathologies, limitations including low signalto-noise ratio and high non-specific binding has addressed for the synthesis of second-and third-generation TSPO-specific radiopharmaceuticals, linked to [ 11 C] or [ 18 F] and including (Luo et al, 2018;Singhal et al, 2018;Best et al, 2019). Similarly, different studies have reported selective microglial uptake of these tracers in multiple sclerosis animal models and patients (Hagens et al, 2018;Herranz et al, 2019;Nack et al, 2019), amyotrophic lateral sclerosis (Zürcher et al, 2015;Datta et al, 2017), Alzheimer's disease (Alam et al, 2017;Keller et al, 2018;Focke et al, 2019), and Lyme disease on humans (Coughlin et al, 2018), and stroke experimental models (Miyajima et al, 2018), with more discordant results for psychiatric patients, suffering from schizophrenia (Di Biase et al, 2017;Hafizi et al, 2017;Ottoy et al, 2018;Selvaraj et al, 2018) and major depression (Li et al, 2018), probably due to the different stage of disease. Interestingly, one study on fibromyalgia subjects attempts to demonstrate specificity of TSPO tracers for microglia, considering that an high expression of this molecule was also detected in activated astrocytes (Albrecht et al, 2019).…”