Histopathological correlates of magnetic resonance imaging-defined chronic perinatal white matter injury

Objective: Although magnetic resonance imaging (MRI) is the optimal imaging modality to define cerebral white-matter injury (WMI) in preterm survivors, the histopathological features of MRI-defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of preoligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation. Methods: We employed a preterm fetal sheep model of global cerebral ischemia in which acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically- defined lesions with contrast-weighted and diffusion-weighted high-field ex vivo MRI data. Results: Despite mild delayed preOL degeneration, preOL density recovered to control levels by 7 days after ischemia and was â2 fold greater at 14 days. However, premyelinating OLs were significantly diminished at 7 and 14 days. WMI evolved to mostly gliotic lesions where arrested preOL differentiation was directly proportional to the magnitude of astrogliosis. A reduction in cerebral WM volume was accompanied by four classes of MRI-defined lesions. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non-necrotic injury. High-field MRI defined 2 novel hypointense signal abnormalities on T ₂-weighted images that coincided with microscopic necrosis or identified astrogliosis with high sensitivity and specificity. Interpretation: These studies support the potential of high-field MRI for early identification of microscopic necrosis and gliosis with preOL maturation arrest, a common form of WMI in preterm survivors.