Widespread Glial Activation in Primary Progressive Multiple Sclerosis Revealed by ¹⁸F-PBR06 PET

A Clinically Feasible, Individualized Approach

Abstract

A 64-year-old man with primary progressive multiple sclerosis (Expanded Disability Status Scale 3.5) underwent PET using ¹⁸F-PBR06, a second-generation 18-kDa translocator protein ligand targeting activated brain microglia and astrocytes. Voxel-by-voxel statistical comparison of patient’s PET images (acquired 60–90 minutes postinjection) with a healthy control data set was performed to generate a 3-dimensional z-score map of increased radiotracer uptake, which showed widespread increased glial activation in normal-appearing cerebral white matter, white matter lesional and perilesional areas, brainstem and cerebellum. In contrast, patient’s 3-T MRI scan showed only a few small white matter brain lesions without contrast enhancement.

FIGURE 1: Widespread glial activation in a primary progressive multiple sclerosis (PPMS) patient with few lesions on MRI. Transverse and sagittal fluid-attenuated inversion recovery MRI slices of a 64-year-old PPMS patient show normal-appearing white matter (NAWM) (A, B) except for a few fluid-attenuated inversion recovery bright lesions (C, D, crosshairs), which are seen in right periventricular white matter (WM) and medulla. Z-score maps of increased ¹⁸F-PBR06 PET uptake (thresholded at z > 4.0) superimposed on MRI (E–G) reveal widespread increased radiotracer uptake in NAWM (arrowheads). Additionally, there is focal increased uptake corresponding to a right periventricular WM lesion (G, arrow) and in a perilesional area in the medulla (H, arrow). A focal area of increased ¹⁸F-PBR06 uptake in the midbrain (H, arrowhead) has no corresponding MRI abnormality (D). In contrast, an age- and genotype-matched healthy control (HC) shows no significant clusters of voxels with increased radiotracer uptake (I–K). The PPMS patient and HC are both medium-affinity binders for rs6971 polymorphism¹ known to affect the ligand’s binding to the translocator protein (TSPO) on activated microglia and astrocytes. Approximately 10% to 15% of patients with multiple sclerosis (MS) present with the primary progressive phenotype of the disease, clinically characterized by gradually progressive symptoms from disease onset.² Pathologically, diffuse microglial activation and astrocytosis are characteristic of PPMS but are not detected by routine MRI.³ Similarly, PPMS patients have higher proportions of mixed active/inactive lesions with perilesionally accumulated activated microglia on pathological examination, which are also not seen on routine MRI.⁴ This case supports the ability of ¹⁸F-PBR06 PET to reveal neuroinflammation in NAWM in absence of MRI abnormalities and in lesional and perilesional WM, consistent with neuropathology in PPMS. ¹⁸F-PBR06 is a second-generation TSPO PET ligand that has been shown to represent increased glial (including microglial and astrocytic) activation in various disease states and disease models, including MS.^5,6 Other TSPO PET ligands such as ¹¹C-PK11195 and ¹¹C-PBR28 have been shown to detect neuroinflammatory aspects of white and gray matter pathology in MS,⁵ but TSPO PET has not been extensively studied in PPMS.^{5,7 18}F-PBR06 has the advantage of a longer radiotracer half-life and better signal-to-noise ratio, as compared with ¹¹C-labeled TSPO ligands. No previous cases of glial activity in PPMS using ¹⁸F-PBR06 PET have been reported. While aging can be associated with increased glial activity, the age- and genotype-matched HC (I–K) demonstrated no significant clusters of voxels with increased ¹⁸F-PBR06 uptake. Further, despite the cumulative evidence on the role of TSPO PET imaging in MS,^5,7 individualized approaches for TSPO PET image analyses have been overlooked. In comparison, individualized parametric 3-dimensional z-score mapping, based on comparison to HC database, has been utilized for brain ¹⁸F-FDG PET imaging and has been shown to improve the diagnostic accuracy in clinical circumstances, for example, in detecting patients with mild cognitive impairment and Alzheimer’s disease.⁸ This case demonstrates that short-duration, static ¹⁸F-PBR06 PET imaging can demonstrate widespread increased glial activation in PPMS using a clinically feasible, individualized z-score mapping approach, similar to the approaches used in ¹⁸F-FDG PET literature. Further studies of ¹⁸F-PBR06 in MS are urgently warranted.