Phagocytic monocyte-derived macrophages associate with the nodes of Ranvier and initiate demyelination while microglia clear debris and display a suppressed metabolic gene signature in EAE.

Objective To determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis (MS) brains. Methods 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 images (“T2T1MTR 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/macrophages, astrocytes, plasma proteins and blood vessels. Results Forty-eight ROIs from four secondary progressive MS brains were analyzed. Sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged MHCII(+) microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area and axonal counts. Excluding T2T1MTR 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. Interpretation The pathologic substrates for MRI abnormalities in NAWM 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.

Our data suggest that the distinct mononuclear phagocytic cell response seen in cerebral X-ALD results, at least in part, from aberrant signaling to cognate receptors on microglia. Our findings support a hypothesis that microglial apoptosis in perilesional white matter represents an early stage in lesion evolution and may be an appropriate target for intervention in X-ALD patients with evidence of cerebral demyelination.

Cortical pathology represents a distinct feature of progressive multifocal leukoencephalopathy. Similarities and differences with regard to multiple sclerosis cortical pathology were noted and may be informative regarding the pathogenesis of both disorders.