Demyelinated lesion associated compartmental inflammation in progressive multiple sclerosis brains

The pathogenesis of progressive multiple sclerosis (PMS) involves aggregates of peripheral and innate immune cells that are collectively referred to as compartmental inflammation. Sites include the meninges, perivascular spaces of vessels, choroid plexus, and borders of demyelinated lesions. Iron-laden activated microglia/macrophages that border cerebral white matter (WM) lesions appear as paramagnetic rims (PRLs) on magnetic resonance imaging. PRLs have been associated with lesion expansion and are considered as a target of brain-penetrable therapies in people with MS. Less is known about inflammatory compartments Bordering cortical lesions. The objective of this retrospective study is to describe the location and morphology of MHC Class II-positive cells in 334 demyelinated lesions from 22 PMS brains. Activated microglia bordered Type III subpial lesions (cortical layers I through III demyelinated) and cortical portions of leukocortical lesions. Activated microglia/macrophages lined the border of chronic active WM lesions, WM portions of leukocortical lesions, and Type IV subpial lesions (all six cortical layers demyelinated). Type IV subpial lesions were lined by activated microglia/macrophages that resided in subcortical WM and were always contiguous with Type III subpial lesions. The location in WM or cortex, rather than lesion type, determined the cellular composition of inflammatory compartments. Since the majority of subpial lesions stop at cortical layer IV and Type IV subpial lesions do not invade subcortical WM, compartments bordering subpial lesions are often associated with lesion stability. Iron was enriched in a subpopulation of inflammatory compartments bordering WM and Type IV subpial lesions, as well as at the border of myelinated cortex and subcortical WM. These myelinated borders were not enriched in microglia and iron was diffusely distributed, providing evidence that iron enrichment is not always associated with lesion expansion nor compartmental inflammation. These data will aid in designing imaging outcome measures for clinical trials targeting inflammatory compartments in PMS.