Journal Article

In vivo assessment of neuroinflammation in progressive multiple sclerosis: a proof of concept study with 18FDPA714 PET

Windhorst, Albert D., Reekie, Tristan A., van Dam, Anne-Marie, van Berckel, Bart N. M., Wijburg, Martijn T., Yaqub, Maqsood, Schober, Patrick, Steenwijk, Martijn D., Lammertsma, Adriaan A., Hagens, Marloes H. J., Golla, Sandeep V., Schuit, Robert C., Kassiou, Michael, Killestein, Joep, Brevé, John J. P., Barkhof, Frederik, Heijtel, Dennis

2018

Overview

Background Over 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 [ 18 F]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. Methods All 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 [ 18 F]DPA714, including both continuous on-line and manual arterial blood sampling to obtain metabolite-corrected arterial plasma input functions. Results The optimal model for quantification of [ 18 F]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 [ 18 F]DPA714 masks its relatively small specific signal. Conclusion The TSPO radioligand [ 18 F]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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: [18F]DPA714 / Affinity / Binding sites / Biomedical and Life Sciences / Biomedicine / Blood / Blood-brain barrier / Brain - diagnostic imaging / Brain research / Encephalitis - diagnostic imaging / Encephalitis - etiology / Female / Fluorodeoxyglucose F18 - pharmacokinetics / Gene polymorphism / Humans / Immunology / Inflammation / Kinetics / Magnetic Resonance Imaging / Male / Medical imaging / Microglia / Middle Aged / Multiple sclerosis / Multiple Sclerosis - complications / Multiple Sclerosis - diagnostic imaging / Neurobiology / Neuroinflammation / Neurology / Neurosciences / NMR / Nuclear magnetic resonance / Plasma / Polymorphism / Positron emission tomography / Proof of Concept Study / Pyrazoles - pharmacokinetics / Pyrimidines - pharmacokinetics / Statistics, Nonparametric / Studies / Substantia alba / TSPO / TspO gene