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

A Clinically Feasible, Individualized Approach

Singhal, Tarun MD∗,†; Rissanen, Eero MD, PhD; Ficke, John BA; Cicero, Steven BS; Carter, Kelsey MSN; Weiner, Howard L. MD

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doi: 10.1097/RLU.0000000000003398
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Abstract

FIGURE 1
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 (EG) 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 (IK). 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 18F-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 (IK) 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.

REFERENCES

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      Keywords:

      astrocytes; PPMS; microglia; neuroinflammation; TSPO PET

      Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.