PL-01 * A PRECLINICAL JUVENILE RAT MODEL OF BRAIN INJURY AFTER FRACTIONATED WHOLE BRAIN IRRADIATION

Abstract

BACKGROUND: Late effects of radiotherapy in survivors of pediatric brain tumors are life-long and debilitating. We describe the behavior and imaging characteristics of a rat model given fractionated whole brain radiation equivalent to doses used to treat children with high-risk medulloblastoma. METHODS: One month-old Fischer rats were given 9 fractions of either 0 or 3 Gray (Gy). A third group was given eight 3Gy fractions followed by a single 10Gy “top off” to serve as a positive control. The 27Gy dose is biologically equivalent to 36Gy given to children. The open-field exploration task and the elevated plus maze were performed at 4 months post-irradiation. Declarative memory was tested by novel object recognition at 4- and 7-months post-irradiation. Magnetic resonance imaging, including diffusion tensor imaging (DTI) and spectroscopy (MRS), was obtained at baseline, 4-, and 7-months post-irradiation. RESULTS: 4 months post-irradiation, there were no differences in the open-field exploration task among the groups. Both the 27Gy (p = 0.002) and 34Gy (p = 0.04) groups demonstrated less exploration of the open arms of the elevated plus maze. There were no differences in novel object recognition at 4 months, but both irradiated groups demonstrated deficits by 7 months post-irradiation (p27 = 0.02, p34 = 0.02). Fractional anisotropy of the corpus callosum at 7 months post-irradiation was decreased only in the 34Gy group (p = 0.02) and not in the 27Gy group. N-acetyl aspartate remained higher than controls at 7-months post-irradiation in both hippocampus (p27 < 0.01, p34 < 0.03) and corpus callosum (p27 < 0.08, p34 < 0.04). CONCLUSIONS: This model of a juvenile rat given fractionated, clinically-relevant doses of radiation displays cognitive deficits described in survivors of medulloblastoma who have received radiotherapy. Imaging characteristics indicate a potential disruption of the normal developmental myelination by MRS that correlates with memory deficits and may be useful for evaluating novel therapeutic strategies of radiation mitigation.