Title | QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Gillen KM, Mubarak M, Park C, Ponath G, Zhang S, Dimov A, Levine-Ritterman M, Toro S, Huang W, Amici S, Kaunzner UW, Gauthier SA, Guerau-de-Arellano M, Wang Y, Nguyen TD, Pitt D |
Journal | Ann Clin Transl Neurol |
Volume | 8 |
Issue | 4 |
Pagination | 877-886 |
Date Published | 2021 Apr |
ISSN | 2328-9503 |
Keywords | Adult, Biomarkers, Cells, Cultured, Female, Humans, Induced Pluripotent Stem Cells, Iron, Magnetic Resonance Imaging, Male, Microglia, Middle Aged, Multiple Sclerosis, Neuroinflammatory Diseases, White Matter |
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. |
DOI | 10.1002/acn3.51338 |
Alternate Journal | Ann Clin Transl Neurol |
PubMed ID | 33704933 |
PubMed Central ID | PMC8045922 |
Grant List | UL1 TR001863 / TR / NCATS NIH HHS / United States R03 AI151769 / AI / NIAID NIH HHS / United States S10 OD021782 / OD / NIH HHS / United States R01 NS102267 / NS / NINDS NIH HHS / United States R01 NS105144 / NS / NINDS NIH HHS / United States R01 AI121405 / AI / NIAID NIH HHS / United States R01 NS090464 / NS / NINDS NIH HHS / United States |