Total-body Irradiation Reduces Cerebrovascular Reactivity in Rhesus Macaques (Macaca mulatta).

Abstract

Radiation-induced brain injury (RIBI) is partially defined by vascular injury, which contributes to long-term cognitive decline. RIBI is irreversible and progressive, highlighting the importance of early identification. Magnetic resonance imaging provides an opportunity to noninvasively detect vascular injury. We used pseudo-continuous arterial spin labeling to evaluate the effects of single dose total-body irradiation (TBI) or partial-body irradiation (5% lower limb sparing) on cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) in 123 rhesus macaques (Macaca mulatta). Of these, 30 were unirradiated controls (22 male, 8 female) and 93 received 1.14-8.5 Gy TBI or 9-10 Gy partial-body irradiation (64 male, 29 female). The age of males ranged from 5-25 years (median unirradiated = 10.1 years; median irradiated = 9.9 years); the age of females ranged from 5-25 years (median unirradiated = 18.7 years; median irradiated = 9.9 years). Radiation effects on CBF and CVR were also assessed in an age-matched subset of males aged 7-12 years (14 controls, 46 TBI). To further characterize radiation-induced vascular change, GLUT-1-stained sections of frontal lobe and hippocampus from 21 (11 control, 10 irradiated) separate animals were evaluated for differences in microvessel density. In 7-12-year-old males, irradiation significantly affected CVR: mean CVR was 4.5% in controls versus 3.6% in irradiated animals. Among all controls, CVR declined significantly across age in both sexes (0.17% per year in males and 0.36% per year in females), whereas CVR did not change with age in irradiated animals. In females, both age and irradiation significantly influenced CVR, and a significant interaction was observed. Neither age nor irradiation significantly affected CBF in males or females. Furthermore, no radiation-induced differences in microvessel density were detected in the frontal lobe or hippocampus. Our findings suggest that CVR decreases with age in macaques, supporting age-related neurodegeneration related to vascular change. Additionally, TBI at doses ≤8.5 Gy impaired CVR in male macaques, highlighting the utility of measuring CVR for detecting radiation-induced vascular injury and allowing for early intervention to mitigate RIBI.