P09.18.A EFFECTS OF HEMI-BRAIN IRRADIATION ON CEREBRAL BLOOD FLOW, VASCULAR INTEGRITY, AND RECOGNITION MEMORY IN NAÏVE MICE

Abstract BACKGROUND Despite playing a critical role in curative and palliative treatment of brain tumours, radiotherapy (RT) damages peritumoral normal brain tissue, which contributes to cognitive decline in up to 90 % of those who survive past 6 months after treatment. Our recent systematic review indicates that brain irradiation induces a wide range of damage on the neurovascular unit, i.e. the blood-brain barrier (BBB) and neural tissue compartments. Here, we aimed to examine the early and late effects of RT on cognition, cerebral blood flow, vascular density, BBB integrity and microglial activation. METHODS Naïve male C57BL/6 mice (n = 8 per group, 26-weeks-old) were X-irradiated with a single dose of 20 Gy (or 0 Gy) to the right hemisphere. Animals underwent novel object recognition testing and magnetic resonance imaging (MRI) at baseline, 1-week, 2-, 4- and 6-months post-irradiation to examine recognition memory and cerebral blood flow (CBF) changes. At the end of the experiment, brain tissues were harvested and stained for markers of vascular damage, including lectin and occludin coverage, and neuroinflammation, including microglia perimeter and distance to nearest vessel. ANOVA were performed to assess the effects of radiotherapy, timepoint or brain region on behavioural, MRI and histological metrics. RESULTS There was a significant main effect of RT on recognition memory (p < 0.0001). Comparisons between treatments at all timepoints showed differences (p < 0.05) except at baseline (p > 0.99) and 6 months post-RT (p = 0.64). There was a significant effect of RT on CBF only at the 2-month time point in left (p = 0.0193) and right (p = 0.0124) white matter. Immunofluorescence analysis of tissue harvested at 6 months showed no difference in vessel area, occudin area, microglial perimeter or microglia-vessel distance between RT and control groups. CONCLUSION In naïve mice, brain irradiation causes prolonged reduction in recognition memory, which recovers to control levels by 6 months. Changes in cerebral blood flow appear transient, detectable only at 2 months post-RT, and localised only to white matter. Histological analysis of tissue harvested 6 months post-RT showed no signs of vascular changes. Further examination of brain tissue changes at more acute timepoints, and in more realistic settings (e.g., tumour-bearing models) will broaden our understanding of how cognitive decline occurs after RT.