Association between chronic active lesions and gray matter pathology in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a leading cause of neurological disability particularly among young adults, traditionally considered a white matter (WM) disease. However, recent research highlights the role of gray matter (GM) pathology and diffuse neuroinflammation in disease progression. Chronic active lesions (CALs), including paramagnetic rim lesions (PRLs), are associated with persistent microglial activation and increased disability. GM pathology plays a crucial role in disease progression in MS, but it is unclear whether this occurs independently or as a secondary consequence of WM damage. This study investigated the impact of WM CALs, detected with MRI and TSPO-PET, on GM atrophy and synaptic density in 79 MS patients and 26 healthy controls. MS patients underwent MRI with quantitative susceptibility mapping, and TSPO-PET imaging with [11C]PK11195-ligand to assess microglia activity. A subset (10 MS / 8 HCs) underwent [11C]UCB-J imaging for synaptic density assessment. Clinical and cognitive assessments were performed. PRLs were identified in 48% of MS patients. Compared to HCs, MS patients exhibited increased atrophy and TSPO-PET binding in several WM and GM regions, alongside reduced UCB-J-PET binding in cortical and deep GM. PRL+ patients demonstrated worse clinical outcomes, greater lesion burden, and more pronounced GM atrophy and microglial activation. CAL-related imaging variables correlated significantly with deep GM atrophy, and inversely with synaptic density. Regression models identified PRL count, age and disease duration as predictors of cognitive decline (R2=0.412, p<0.05) and thalamic atrophy (R2=0.366, p<0.001). These findings highlight the destructive nature of CALs in MS and underscore their potential as clinically relevant biomarkers in MS.