Imaging Outcomes for Phase 2 Trials Targeting Compartmentalized Inflammation

Abstract

This comprehensive review aims to explore imaging outcome measures targeting compartmentalized inflammation in Phase 2 clinical trials for multiple sclerosis (MS). The traditional primary imaging outcomes used in Phase 2 MS trials, new or enhancing white matter lesions on MRI, target the effects of peripheral inflammation, but the widespread inflammation behind a mostly closed blood-brain barrier is not captured. This review discusses several emerging imaging technologies that could be used as surrogate markers of compartmentalized inflammation, targeting chronic active lesions, meningeal inflammation, and innate immune activation within the normal-appearing white matter and gray matter. The integration of specific imaging outcomes into Phase 2 trials can provide a more accurate assessment of treatment efficacy, ultimately contributing to the development of more effective therapies for MS.

Keywords: Phase 2 trials; compartmentalized inflammation; multiple sclerosis; outcome measure.

Figure 1.

Paramagnetic Rim lesions at 7T. Axial T2*-weighted motion and B0 corrected imaging at 0.5mm isotropic resolution, magnitude and unwrapped filtered phase images. (A) A hypointense signal surrounds the hyperintense lesion core in magnitude, yellow rectangle, hypointense rim in phase observed in 3 planes. (B) A hypointense signal surrounds the hyperintense lesion core in magnitude, yellow rectangle, hypointense rim in phase, along central vein can be observed along the center of the lesion. (C) Hyperintense lesion core in magnitude, yellow rectangle, hypointense rim in phase.

Figure 2.

Representative images from a participant with RRMS showing improved visualization of leptomeningeal enhancement (LME) on Real-IR compared to T2-FLAIR. A spread/fill LME on both post-GBCA T2-FLAIR and Real-IR (A), a nodular LME on both T2-FLAIR and Real-IR (B). An LME mostly visible on Real-IR (C) shown enlarged in 3 planes.