QSM as a biomarker of chronic glial activation in multiple sclerosis – An in vivo comparison of QSM and TSPO-PET

Abstract

Investigations of chronic microglial activation and co-localization of iron in multiple sclerosis (MS) have been mostly focused on paramagnetic rim lesions (PRLs). Findings of diffuse inflammation in normal-appearing white matter (NAWM) and iron deposition in deep grey matter (DGM) suggest that valuable insights could be gained from studying them. The current cross-sectional study investigated quantitative susceptibility mapping (QSM) data in a sample of 54 relapsing-remitting MS (RRMS) patients, 13 progressive MS (PMS) patients and 24 healthy controls (HC). 18 kDa translocator protein positron emission tomography (TSPO-PET) and advanced magnetic resonance imaging (MRI) QSM complement each other by providing a look into the spatial distribution of different disease-related mechanisms. Comparing different disease phenotypes with healthy controls allows for identification of changes indicative of pathology, thereby also partially contributing to our understanding of changes between disease stages. Pairwise group differences were found in QSM and TSPO-PET. Compared to PMS patients those with RRMS had lower QSM values in the whole brain (corr p = 0.043), NAWM (corr p = 0.026) and pallidum (corr p = 0.021). HC also had significantly lower QSM values in the pallidum (corr p = 0.008) than PMS patients. For TSPO-PET, RRMS had lower values in whole brain (corr p = 0.007), NAWM (corr < 0.001), pallidum (corr p = 0.003) and thalamus (corr p = 0.006) than PMS patients. Pallidum (corr p = 0.024) and NAWM (corr p = 0.001) had lower values for HC compared to PMS patients. Associations between TSPO-PET and QSM in NAWM were strongest for patients with PRLs (n = 28, ρ = 0.489, raw p = 0.008) and non-Gadolinium enhancing (Gd-) lesions (n = 35, ρ = 0.406, p = 0.016). Exploratory analysis of the relationship between QSM and clinical as well as imaging-derived variables revealed significant correlations mainly for DGM structures. Correlations comprised blood biomarkers, disease characteristics and age. DVR values also correlated with various clinical and imaging-derived variables including EDSS, which didn’t correlate with QSM values. These findings support the idea of a diffuse effect of chronic lesions (PRLs and Gd- lesions) on NAWM and clinically relevant iron dysregulation in DGM in MS. Our results indicate particularly marked changes in progressive patients compared to RRMS and HC. Therefore, future studies should aim to better understand the roles of iron and microglial activity and their interaction in MS disease progression.