QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions

Abstract

Background Inflammation in chronic active lesions occurs behind a closed blood–brain barrier and cannot be detected with MRI. Activated microglia are highly enriched for iron and can be visualized with quantitative susceptibility mapping (QSM), an MRI technique used to delineate iron. Objective To characterize the histopathological correlates of different QSM hyperintensity patterns in MS lesions. Methods MS brain slabs were imaged with MRI and QSM, and processed for histology. Immunolabeled cells were quantified in the lesion rim, center, and adjacent normal‐appearing white matter (NAWM). Iron+ myeloid cell densities at the rims were correlated with susceptibilities. Human‐induced pluripotent stem cell (iPSC)‐derived microglia were used to determine the effect of iron on the production of reactive oxygen species (ROS) and pro‐inflammatory cytokines. Results QSM hyperintensity at the lesion perimeter correlated with activated iron+ myeloid cells in the rim and NAWM. Lesions with high punctate or homogenous QSM signal contained no or minimally activated iron− myeloid cells. In vitro, iron accumulation was highest in M1‐polarized human iPSC‐derived microglia, but it did not enhance ROS or cytokine production. Conclusion A high QSM signal outlining the lesion rim but not punctate signal in the center is a biomarker for chronic inflammation in white matter lesions.

Quantitative susceptibility mapping captures chronic multiple sclerosis rim lesions with greater myelin damage: Comparison with high-pass filtered phase MRI

“…The copyright holder for this preprint this version posted May 25, 2021. ; https://doi.org/10.1101/2021.05.23.21257680 doi: medRxiv preprint the lesion periphery surrounding a relatively inactive demyelinated lesion center (4)(5)(6). The paramagnetic rim iron magnetized inside an MRI scanner creates a tissue magnetic field that is the spatial convolution of the iron-related susceptibility distribution with the dipole kernel but dominated by the strong and smooth background field (15).…”

“…Both HPF phase and QSM can be derived from the same GRE source data and have shown the presence of iron-positive pro-inflammatory activated microglia and macrophages in the lesion periphery surrounding a relatively inactive demyelinated lesion center (4-6). The paramagnetic rim iron magnetized inside an MRI scanner creates a tissue magnetic field that is the spatial convolution of the iron-related susceptibility distribution with the dipole kernel but dominated by the strong and smooth background field (15).…”

“…Following the transition into the chronic stage after BBB closure, some lesions have the ability to self-repair tissue injury, while others continue to undergo demyelination, which has been attributed to persistent low-grade microglial inflammation behind the sealed BBB (3). An important subset of chronic active lesions have a relatively inactive core surrounded by a slowly expanding rim of continuing demyelination and axonal loss infiltrated by iron-laden activated microglia and macrophages (3)(4)(5)(6)(7).…”

The Macrophage Iron Signature in Health and Disease

“…During development, microglia store iron when myelination is not active, and transfer iron to oligodendrocytes when the myelination proceeds [259]. Iron accumulation in microglia has also been observed in different neurodegenerative diseases, among others Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) [260][261][262].…”

Disease Correlates of Rim Lesions on Quantitative Susceptibility Mapping in Multiple Sclerosis

“…Quantitative susceptibility mapping (QSM) 14 is an effective post-processing technique for GRE data that directly maps the various sources of susceptibility by solving the field-to-source inversion problem 15 and providing quantification and localization of brain iron [16][17][18][19] . Lesions with a hyperintense rim (rim+) on QSM have increased inflammation on PK11195-PET, with histopathological and in vitro studies confirming a rim of inflammatory cells and more tissue damage on myelin water fraction imaging 15,20,21 . The quantitative nature of QSM provides a unique opportunity to capture time-dependent changes of rim lesions, as their susceptibility remains high even after years of initial detection and slowly decays over time 10,[22][23][24] .…”