In vivo assessment of neuroinflammation in progressive multiple sclerosis: a proof of concept study with [18F]DPA714 PET

Abstract

BackgroundOver the past decades, positron emission tomography (PET) imaging has become an increasingly useful research modality in the field of multiple sclerosis (MS) research, as PET can visualise molecular processes, such as neuroinflammation, in vivo. The second generation PET radioligand [18F]DPA714 binds with high affinity to the 18-kDa translocator-protein (TSPO), which is mainly expressed on activated microglia. The aim of this proof of concept study was to evaluate this in vivo marker of neuroinflammation in primary and secondary progressive MS.MethodsAll subjects were genotyped for the rs6971 polymorphism within the TSPO gene, and low-affinity binders were excluded from participation in this study. Eight patients with progressive MS and seven age and genetic binding status matched healthy controls underwent a 60 min dynamic PET scan using [18F]DPA714, including both continuous on-line and manual arterial blood sampling to obtain metabolite-corrected arterial plasma input functions.ResultsThe optimal model for quantification of [18F]DPA714 kinetics was a reversible two-tissue compartment model with additional blood volume parameter. For genetic high-affinity binders, a clear increase in binding potential was observed in patients with MS compared with age-matched controls. For both high and medium affinity binders, a further increase in binding potential was observed in T2 white matter lesions compared with non-lesional white matter. Volume of distribution, however, did not differentiate patients from healthy controls, as the large non-displaceable compartment of [18F]DPA714 masks its relatively small specific signal.ConclusionThe TSPO radioligand [18F]DPA714 can reliably identify increased focal and diffuse neuroinflammation in progressive MS when using plasma input-derived binding potential, but observed differences were predominantly visible in high-affinity binders.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1352-9) contains supplementary material, which is available to authorized users.

Chronic inflammation in multiple sclerosis — seeing what was always there

“…Stratification of the population by genotype also can be used for 18 F-DPA714 PET, but the dynamic range of the signal with this radioligand in MS is lower than that for 11 C-PBR28, which limits its practical application to people who are homozygous for the 'high-binding' TSPO allele 165 .…”

Individual Mapping of Innate Immune Cell Activation Is a Candidate Marker of Patient-Specific Trajectories of Worsening Disability in Multiple Sclerosis

“…The pyrazolopyrimidine 18 F-DPA-714 (12) is a fluorinated second-generation TSPO tracer, which allows a reliable kinetic modelling in humans (13), and a noninvasive quantification through the extraction of reference regions (14,15). In a recent pilot study, 18 F-DPA-714 PET could reliably identify focal and diffuse neuroinflammation (16). In this study, we investigated a group of 37 patients with relapsing or progressive MS and a group of healthy controls with 18 F-DPA-714 PET.…”

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).…”