Smoldering neuroinflammation in progressive multiple sclerosis: mechanisms, imaging biomarkers, and therapeutic...

Progressive multiple sclerosis (MS) remains a major therapeutic challenge because disability often continues to accumulate despite effective control of relapses and new focal inflammatory lesions. This dissociation suggests that progression is driven not only by acute inflammation, but also by a distinct process increasingly termed smoldering neuroinflammation. Recent evidence supports chronic active lesions as an important but non-exclusive pathological substrate of this process. These lesions are characterized by persistent lesion-edge inflammation, slowly expanding tissue injury, iron-laden myeloid cells, astrocyte-immune crosstalk, and incomplete repair. Importantly, this inflammatory activity is not restricted to isolated white matter plaques, but is spatially compartmentalized across the central nervous system, involving interactions among white matter lesions, meninges, cortex, and subcortical regions. Advances in susceptibility-based MRI and PET imaging now allow in vivo assessment of imaging-related correlates of this otherwise hidden pathology, including paramagnetic rim lesions (PRLs), slowly expanding lesions (SELs), and TSPO-PET-defined inflammatory activity. Although these biomarkers overlap only partially, they provide complementary insights into lesion composition, structural expansion, and metabolic inflammation. Accumulating studies further suggest that current disease-modifying therapies incompletely control established chronic lesion biology, while other inflammatory-independent or age-related neurodegenerative processes may also contribute to progression. In this review, we discuss the pathological basis, imaging correlates, and therapeutic implications of smoldering neuroinflammation in progressive MS.