Translocator protein PET imaging for glial activation in multiple sclerosis

Abstract

Glial activation in the setting of central nervous system inflammation is a key feature of the multiple sclerosis (MS) pathology. Monitoring glial activation in subjects with MS, therefore, has the potential to be informative with respect to disease activity. The translocator protein 18 kDa (TSPO) is a promising biomarker of glial activation that can be imaged by positron emission tomography (PET). To characterize the in vivo TSPO expression in MS, we analyzed brain PET scans in subjects with MS and healthy volunteers in an observational study using [(11)C]PBR28, a newly developed translocator protein-specific radioligand. The [(11)C]PBR28 PET showed altered compartmental distribution of TSPO in the MS brain compared to healthy volunteers (p = 0.019). Focal increases in [(11)C]PBR28 binding corresponded to areas of active inflammation as evidenced by significantly greater binding in regions of gadolinium contrast enhancement compared to contralateral normal-appearing white matter (p = 0.0039). Furthermore, increase in [(11)C]PBR28 binding preceded the appearance of contrast enhancement on magnetic resonance imaging in some lesions, suggesting a role for early glial activation in MS lesion formation. Global [(11)C]PBR28 binding showed correlation with disease duration (p = 0.041), but not with measures of clinical disability. These results further define TSPO as an informative marker of glial activation in MS.

Fig. 1

Global and compartmental [¹¹C]PBR28 binding in subjects with MS compared to healthy volunteers. a Mean (±SD) brain parenchymal [¹¹C] PBR28 binding in subjects with multiple sclerosis (MS) compared to healthy volunteers (HV). b The ratios of white matter to gray matter fraction [¹¹C]PBR28 binding (WM/GM) in subjects with MS compared to HV

Fig. 2

Gadolinium contrast-enhancing lesions show focal increase in [¹¹C]PBR28 binding. a Fluid-attenuated inversion recovery (FLAIR) and post-contrastT₁-weighted (post-contrast T₁) MRI, and [¹¹C] PBR28 PET from a subject with MS (MS3) showing increased [¹¹C] PBR28 binding in the areas corresponding to gadolinium-enhancing lesion (arrows). b [¹¹C]PBR28 binding in gadolinium contrast-enhancing lesions (CEL) compared to contralateral normal-appearing white matter (NAWM). Error bars indicate ±SD. c MRI co-registered baseline-to-follow-up [¹¹C]PBR28 V_T difference map (left) and post-contrast T₁-weighted MRI (right) showing a region of interval increase in [¹¹C]PBR28 binding corresponding to a gadolinium contrast-enhancing lesion (arrows). d Post-contrast T₁-weighted MRI (left) and co-registered [¹¹C]PBR28 V_T difference map (center) with increased [¹¹C]PBR28 binding that precedes a gadolinium enhancement of the same region a month later (right)

Fig. 3

Correlation between disease duration and mean brain parenchymal [¹¹C]PBR28 binding in subjects with MS (R²=0.39, p=0.041)