In vivo Magnetization Transfer MRI Shows Dysmyelination in an Ischemic Mouse Model of Periventricular Leukomalacia

Abstract

Periventricular leukomalacia, PVL, is the leading cause of cerebral palsy in prematurely born infants, and therefore more effective interventions are required. The objective of this study was to develop an ischemic injury model of PVL in mice and to determine the feasibility of in vivo magnetization transfer (MT) magnetic resonance imaging (MRI) as a potential monitoring tool for the evaluation of disease severity and experimental therapeutics. Neonatal CD-1 mice underwent unilateral carotid artery ligation on postnatal day 5 (P5); at P60, in vivo T2-weighted (T2w) and MT-MRI were performed and correlated with postmortem histopathology. In vivo T2w MRI showed thinning of the right corpus callosum, but no significant changes in hippocampal and hemispheric volumes. Magnetization transfer MRI revealed significant white matter abnormalities in the bilateral corpus callosum and internal capsule. These quantitative MT-MRI changes correlated highly with postmortem findings of reduced myelin basic protein in bilateral white matter tracts. Ventriculomegaly and persistent astrogliosis were observed on the ligated side, along with evidence of axonopathy and fewer oligodendrocytes in the corpus callosum. We present an ischemia-induced mouse model of PVL, which has pathologic abnormalities resembling autopsy reports in infants with PVL. We further validate in vivo MRI techniques as quantitative monitoring tools that highly correlate with postmortem histopathology.

Selective expression of Narp in primary nociceptive neurons: Role in microglia/macrophage activation following nerve injury

“…For quantifying microglia/macrophage activation, we used the proportional area method (Donnelly et al, 2009; Fatemi et al, 2011) to determine the proportion of the ventral or dorsal horn that was Iba1-positive. In addition, we also monitored Iba1-positive cell counts in these regions.…”

The challenge of understanding cerebral white matter injury in the premature infant

“…More recently, a mouse model using unilateral carotid ligation alone (without hypoxia) at P5 has been developed that produces a bilateral white matter injury with some features of PVL (Fatemi et al, 2011). The authors argue that the relative selectivity for white matter is because the insult is milder and inflicted at an earlier age, although the mortality rate from the injury was 25% and, of the animals that survived, almost 10% suffered large hemispheric strokes and had to be excluded from analysis.…”

Diffusion Tensor Imaging Abnormalities in the Cerebral White Matter Correlate with Sex-Dependent Neurobehavioral Deficits in Adult Mice with Neonatal Ischemia

“…For quantification of SMI-32 and MBP immunostaining, semiquantitive densitometry was performed using MCID Core (InterFocus Imaging Ltd, Cambridge, UK), as previously published [15]. After calibration with optical density standards, pictures of 5-6 consecutive axial sections were taken covering the area from the first connection of the corpus callosum to its separation.…”

“…Histologic studies in ligated animals revealed a bilateral microglial response that correlated with maturational arrest in oligodendrocytes with subsequent myelin pallor and a diffuse axonopathy. Apoptosis measured by caspase 3 staining was almost exclusively limited to OPCs within the white matter tracts [15]. Furthermore, we have also shown immediate up-regulation of proinflammatory cytokines [5].…”

“…We have recently reported a mouse model with unilateral carotid artery ligation on postnatal day (P)4 that leads to diffuse but selective bilateral white matter injury [15]. Histologic studies in ligated animals revealed a bilateral microglial response that correlated with maturational arrest in oligodendrocytes with subsequent myelin pallor and a diffuse axonopathy.…”