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

Abstract

Objective Although 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 pre-oligodendrocytes (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 where acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically defined lesions with contrast- 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 ~2 fold greater at 14 days. However, pre-myelinating 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 two novel hypo-intense signal abnormalities on T2-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.

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

“…Note that in many studies hypoxia-ischemia (H/I) (arrow) is administered at 90 to 95 days, which coincides with the high-risk period for periventricular white matter injury (PWMI) at~23 to 32 weeks. preOLs 0 late oligodendrocyte progenitors and docile nature of the sheep supports the feasibility of either in utero or ex vivo neuroimaging studies [46,76].…”

“…The preterm fetal sheep is susceptible to acute [41] and chronic [46] WMI, which is very similar to humans in histopathological features. The fetal sheep cerebrum has a predilection for relatively selective WMI under conditions of moderate cerebral ischemia [41], whereas rodents have a propensity for mixed cerebral injury such that substantial gray matter injury accompanies WMI [47][48][49][50][51][52].…”

“…This preparation generated a spectrum of WMI very similar to that observed from human autopsy studies, as well as a reduction in cerebral WM volume similar to that observed in preterm survivors [116][117][118]. We developed registration algorithms to analyze the histopathological features of 3 classes of MRI-defined lesions identified by ex vivo imaging at high field (12 Tesla) [46]. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non-necrotic WMI.…”

“…In contrast to fetal sheep preparations, the small size of rodents is a major technical limitation for a wide range of invasive physiological measurements, as well as for studies that seek to achieve high resolution neuroimaging by using MRI [46,64]. Thus, it is feasible to study well-defined brain insults in fetal sheep with reliable measurements of blood pressure (BP), oxygenation, cerebral blood flow, and metabolism.…”

“…We used quantitative electron microscopy studies in our preterm fetal sheep model of global cerebral ischemia to define the extent of axonal degeneration in MRI-defined diffuse WMI [53]. During the chronic phase of WMI from this same fetal sheep preparation [46] and human [54], microscopic foci of necrosis were observed that were rich in microglia, but lacked astrocytes or axons. However, no significant axonal degeneration, axonal loss or shift in the distribution of axon calibers was observed by quantitative electron microscopy studies in preterm fetal sheep [53].…”