Comparison of Two Neonatal Ischemic Injury Models Using Magnetic Resonance Imaging

Abstract

Using an 11.7-Tesla magnetic resonance imaging (MRI) scanner in 10-d-old rat pups we report on the evolution of injury over 28 d in a model of neonatal stroke (transient filament middle cerebral artery occlusion, tfMCAO) and a model of hypoxicischemic injury (Rice-Vannucci model, RVM). In both models, diffusion-weighted imaging (DWI) was more sensitive in the early detection of ischemia than T2-weighted imaging (T2WI). Injury volumes in both models were greater on d 1 for DWI and d 3 for T2WI, decreased over time and by d 28 T2WI injury volumes (tfMCAO 10.3% of ipsilateral hemisphere; RVM 23.9%) were definable. The distribution of injury with tfMCAO was confined to the vascular territory of the middle cerebral artery and a definable core and penumbra evolved over time. Ischemic injury in the RVM was more generalized and greater in cortical regions. Contralateral hemispheric involvement was only observed in the RVM. Our findings demonstrate that high-field MRI over extended periods of time is possible in a small animal model of neonatal brain injury and that the tfMCAO model should be used for studies of neonatal stroke and that the RVM does not reflect the vascular distribution of injury seen with focal ischemia. (Pediatr Res 61: 9-14, 2007) C urrent neuroprotective therapies of acute stroke in adults have not proven beneficial and because the delay in diagnosis of neonatal stroke is beyond the current window of opportunity for thrombolytic therapy, it is likely that future neonatal care will focus on delayed treatments implemented hours to days after ischemia. Temporally delayed treatment is even more likely in cases of neonatal ischemia as observable signs are more difficult to assess and observe. As such, being able to serially and noninvasively monitor the evolution of neonatal stroke in humans as well as animal models over weeks to months would be advantageous in studying mechanisms of injury, repair and responses to treatment. Magnetic resonance imaging (MRI) has greatly improved our ability to detect stroke in newborns but its use in neonatal stroke models has been limited by the technical challenges in serially acquiring such data (1,2).The current study used high field strength (11.7T; Tesla) MRI to study the evolution of neonatal hypoxic-ischemic injury over a period of 28 d in two different models. We chose to compare a model of neonatal stroke (tfMCAO, transient filament middle cerebral artery occlusion) to that of the more commonly used model of neonatal hypoxic-ischemic brain injury (RVM, Rice-Vannucci model of unilateral carotid ligation and 1.5 h of hypoxia). We hypothesized that MRI could be used in a small animal model to serially and noninvasively monitor the evolution of injury over 28 d and that neuroimaging could elucidate temporal and spatial patterns of injury in the two models. Specifically, we wished to determine whether there were neuroimaging differences between the two models in: (1) the distribution of injury; (2) the degree of injury in striatum and cortex; (3) the evolut...

Temporal and Regional Evolution of Aquaporin-4 Expression and Magnetic Resonance Imaging in a Rat Pup Model of Neonatal Stroke

“…As visualized by MRI, cytotoxic edema usually precedes the development of vasogenic edema (6,17,18). Deletion of AQP4 appears protective against the development of cytotoxic edema and results in smaller infarct volumes (10).…”

Mechanisms of Perinatal Arterial Ischemic Stroke

“…13,74,78,79 Figure 1B shows that diffusion-weighted MRI depicts expansion of tissue 'at risk' associated with longer MCAO duration. Other MRI modalities have been proven useful in determining the extent of microcirculatory disturbances during MCAO and after reperfusion (perfusion-sensitive MRI), 76 disruption of the blood-brain barrier (BBB) (Gd-enhanced T1W imaging), 76 elucidation of the evolving injury (T2W imaging), 56,73,80 and changes in brain connectivity after injury during the neonatal period (diffusion tensor imaging). 81 Studies in tMCAO and H-I models in neonatal rodents have shown that although the components of injury that induce cell death and brain injury are similar to those occurring in experimental models of preterm injury-excitotoxic, oxidant, and inflammatory components-the targeted cell populations and regions affected by cerebral hypoxia and ischemia are different.…”

Neuroimaging assessment of memory‐related brain structures in a rat model of acute space‐like radiation

“…The variable time course of T2 and ADC responses reveals the underlying tissue pathologic processes. In the setting of cerebral ischemia, previous investigations have shown that the decrease in ADC often returns to normal values (pesduonormalization) while T2 values increase at the 7-day postinjury timepoint (14). In light of our present findings, the neuroimaging interpretations may not be uniform and should be addressed within the context of the triggering pathology.…”

“…ADC values are influenced by a host of intracellular and extracellular constituents that vary with the nature of cellular barriers (32). A variety of brain pathologies can be identified using DWI, including stroke (14) and seizures (13), in which the initial decrease in ADC occurs simultaneously with glial cell proliferation, neurodegeneration, or cytotoxic edema (13,14). At 1 week after 56 Fe exposure, there was a significant drop in brain ADC values in the absence of evident histopathology except for the subtle astrocytic hypertrophy at 4 Gy.…”

“…Evaluation of relaxation times offers a method for investigating neurophysiology and neuropathology in vivo (8,9,11). Diffusion-weighted imaging (DWI) complements the classical anatomical MRI techniques and are sensitive to changes in intracerebral structure and function at early stages of brain injury (12)(13)(14). The quantitative DWI parameter, apparent diffusion coefficient (ADC), is used to characterize water mobility in local tissues (15).…”