The aim of the study was to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters in normal-appearing white matter (NAWM) in brain tissue from patients with secondary progressive multiple sclerosis (MS).
Brain tissues were obtained through a rapid post-mortem protocol that included in situ MRI. Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) Regions that were abnormal on all studied sequences(“T2 T1 MTR lesions”); (2) NAWM regions with slightly-abnormal MTR located close to white matter lesions (“sa-WM Close”); (3) NAWM regions with slightly-abnormal MTR located far from lesions (“sa-WM Far”); and (4) NAWM regions with normal MTR (“NAWM”). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia, astrocytes, plasma proteins and blood vessels.
Forty eight ROIs from four MS brains were analyzed. Sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged activated microglia detected in sa-WM Far, sa-WM Close, and T2 T1 MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area and axonal counts. Excluding T2 T1 MTR lesions from analysis revealed that MTR and DTI measures in non-lesional WM were correlated with activated microglia, but not with axonal or myelin integrity.
Our finding indicate that the pathologic substrates for MRI abnormalities in NAWM of MS brains significantly vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.
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