Longitudinal diffusion tensor and manganese-enhanced MRI detect delayed cerebral gray and white matter injury after hypoxia–ischemia and hyperoxia

Abstract

Background: hypoxia-ischemia (hI) induces delayed inflammation and long-term gray and white matter brain injury that may be altered by hyperoxia. Methods: hI and 2 h of hyperoxia (100% O 2 ) or room air (21% O 2 ) in 7-d-old (P7) rats were studied by magnetic resonance imaging at 7 Tesla during 42 d: apparent diffusion coefficient (aDc) maps on day 1; T 1 -weighted manganese-enhanced images on day 7; diffusion tensor images on days 21 and 42; and T 2 maps at all time points. results: The long-term brain tissue destruction on T 2 maps was more severe in hI+hyperoxia than hI+room air. aDc was lower in hI+hyperoxia vs. hI+room air and sham and was correlated with long-term outcome. Manganese enhancement indicating inflammation was seen in both the groups along with more microglial activation in hI+hyperoxia on day 7. Fractional anisotropy (Fa) in corpus callosum was lower and radial diffusivity was higher in hI+hyperoxia than that in hI+room air and sham on day 21. From day 21 to day 42, Fa and radial diffusivity in hI+hyperoxia were unchanged, whereas in hI+room air, Fa increased and radial diffusivity decreased to values similar to sham. conclusion: hyperoxia caused a more severe tissue destruction, delayed irreversible white matter injury, and increased inflammatory response resulting in a worsening in the trajectory of injury after hI in developing gray and white matter.

Increased expression of inflammatory genes in the neonatal mouse brain after hyperoxic reoxygenation

“…Several groups have found increased brain lesions in neonatal rats after hyperoxic reoxygenation following HI (25,38,39). The increased inflammatory gene response after hyperoxic reoxygenation we found in the present study, supports the evidence that increased inflammation might be one of the contributing factors to the increased brain damage after hyperoxic reoxygenation.…”

Improved Visualization of Neuronal Injury Following Glial Activation by Manganese Enhanced MRI

“…Based on our long standing interest in the links between neuroimmunity and neurodegenerative diseases we reasoned that pathological activation of the immune-competent glial cells could represent an obligatory event for any MEMRI signal enhancements. In support of this idea is a wealth of prior studies demonstrating MEMRI signal enhancements were co-localized with reactive glia (Haapanen et al 2007; Wideroe et al 2009; Wideroe et al 2011; Morken et al 2013). However it was never clear if such signal enhancements resulted from Mn 2+ accumulation in the glial cells directly, or from elevated manganese uptake by neuronal cells stimulated by glial reaction.…”

“…Several groups have studied the relationship between MEMRI signal enhancement and glial reaction in a range of animal models of human disease, including but not limited to, cathepsin D deficiency (Haapanen et al 2007), epilepsy (Immonen et al 2008), ischemia (Wideroe et al 2009; Wideroe et al 2011; Morken et al 2013) and prenatal X-ray exposure (Saito et al 2012). However, results have been varied.…”

“…Despite such potential limitations, significant attempts have been made, in recent years, to use MEMRI in studies of the pathobiology of neurodegenerative diseases utilizing relevant animal models (Bertrand et al 2013; Perez et al 2013; Drobyshevsky et al 2012; Haenold et al 2012; Morken et al 2013; Saito et al 2012; Wideroe et al 2012; Bouilleret et al 2011; Chan et al 2011; Kim et al 2011; Smith et al 2011; Soria et al 2011; Tang et al 2011; Wideroe et al 2011; Inoue et al 2010; Kawai et al 2010; van Meer et al 2010). Nonetheless and paramount to the successful application of MEMRI is not simply the ability to deliver Mn 2+ to the site of interest or of disease but in determining the cell types and cellular mechanisms that engage the ion and produce the signal enhancement observed.…”

Sex differences in brain MRI abnormalities and neurodevelopmental outcomes in a rat model of neonatal hypoxia-ischemia

“…For instance, MRI has been used to demonstrate that hyperoxia exacerbates the tissue destruction that occurs over a 42-day period following HIBI [33], and that treatment with doxycycline appears to reduce the extent of cerebral tissue loss and white matter injury [34]. In addition, MRI has been found capable of detecting acute axonal damage, with apparent diffusion Table 3.…”