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(Stroke. 2008;39:1862.)
© 2008 American Heart Association, Inc.

Original Contributions

Early Diffusion-Weighted MRI as a Predictor of Caspase-3 Activation After Hypoxic–Ischemic Insult in Neonatal Rodents

Michael F. Wendland, PhD; Joel Faustino, BS; Tim West, PhD; Catherine Manabat, BS; David M. Holtzman, MD Zinaida S. Vexler, PhD

From the Departments of Radiology (M.F.W.) and Neurology (J.F., C.M., Z.S.V.), University of California–San Francisco, San Francisco, Calif; and the Departments of Neurology, Molecular Biology & Pharmacology and the Hope Center for Neurological Disorders (T.W., D.M.H.), Washington University School of Medicine, St Louis, Mo.

Correspondence to Zinaida S. Vexler, PhD, University California–San Francisco, Department of Neurology, Box 0663, 521 Parnassus Ave, San Francisco, CA 94143-0663. E-mail Zena.Vexler{at}ucsf.edu

Background and Purpose— Neonatal encephalopathy in human babies is a serious condition associated with permanent neurological deficits. Diffusion-weighted MRI (DWI) is increasingly used for early diagnosis of brain injury in human babies. The relationship between the presence of DWI abnormalities and cellular injury, including apoptosis, during the neonatal period are not well understood. We asked whether the extent of injury depicted on DWI can predict the presence of caspase-3 activation, a quantitative marker of apoptotic injury, after hypoxia–ischemia (H-I) in postnatal day 7 rats.

Methods— Injury volume was determined by DWI at 2 hours, 24 hours, and 7 days after H-I and compared with histology. Caspase-3 activation and microgliosis were determined at 24 hours post-H-I.

Results— DWI-defined lesions (eg, decreased apparent diffusion coefficient) at 24 hours post-H-I correlated with a major increase in caspase-3 activity in the injured hemisphere and predicted injury. A modest but significant increase in caspase-3 activity occurred in the cortex of rats that had no apparent diffusion coefficient decrease in the injured hemisphere but had unilaterally enlarged regions of high apparent diffusion coefficient at the ipsilateral ventricle/white matter interface. Caspase-3 activity was similar in both hemispheres in pups with unchanged DWI.

Conclusions— Abnormal DWI signal at 24 hours post-H-I is predictive of caspase-3 activation and can be used as an indicator that injury involving an apoptotic-like mechanism is present. Our data also suggest that the presence of an enlarged unilateral region with high apparent diffusion coefficient at the ventricle/white matter interface without significant apparent diffusion coefficient decrease in the cortex is a sign of modest caspase-3 activation after H-I.

Key Words: apoptosis • caspase-3 • diffusion-weighted MRI • hypoxia–ischemia • neonate