White Matter is the Predilection Site of Late-Delayed Radiation-Induced Brain Injury in Non-Human Primates

Abstract

Fractionated whole-brain irradiation for the treatment of intracranial neoplasia causes progressive neurodegeneration and neuroinflammation. The long-term consequences of single-fraction high-dose irradiation to the brain are unknown. To assess the late effects of brain irradiation we compared transcriptomic gene expression profiles from nonhuman primates (NHP; rhesus macaques Macaca mulatta) receiving single-fraction total-body irradiation (TBI; n ¼ 5, 6.75-8.05 Gy, 6-9 years prior to necropsy) to those receiving fractionated whole-brain irradiation (fWBI; n ¼ 5, 40 Gy, 8 3 5 Gy fractions; 12 months prior to necropsy) and control comparators (n ¼ 5). Gene expression profiles from the dorsolateral prefrontal cortex (DLPFC), hippocampus (HC) and deep white matter (WM; centrum semiovale) were compared. Stratified analyses by treatment and region revealed that radiation-induced transcriptomic alterations were most prominent in animals receiving fWBI, and primarily affected white matter in both TBI and fWBI groups. Unsupervised canonical and ontologic analysis revealed that TBI or fWBI animals demonstrated shared patterns of injury, including white matter neuroinflammation, increased expression of complement factors and T-cell activation. Both irradiated groups also showed evidence of impaired glutamatergic neurotransmission and signal transduction within white matter, but not within the dorsolateral prefrontal cortex or hippocampus. Signaling pathways and structural elements involved in extracellular matrix (ECM) deposition and remodeling were noted within the white matter of animals receiving fWBI, but not of those receiving TBI. These findings indicate that those animals receiving TBI are susceptible to neurological injury similar to that observed after fWBI, and these changes persist for years postirradiation. Transcriptomic profiling reaffirmed that macrophage/ microglial-mediated neuroinflammation is present in radiation-induced brain injury (RIBI), and our data provide novel evidence that the complement system may contribute to the pathogenesis of RIBI. Finally, these data challenge the assumption that the hippocampus is the predilection site of injury in RIBI, and indicate that impaired glutamatergic neurotransmission may occur in white matter injury.

Reduction of pTau and APP levels in mammalian brain after low-dose radiation

“…Importantly, these findings on early molecular changes in a normal large mammalian brain in the absence of obvious neurohistological changes or macroscopic brain lesions support the hypothesis that early specific molecular changes do occur and are detectable at 4 weeks post-radiation across different regions of the brain. Remarkably, the lower levels of pTau, APP and GAP43 observed across the different examined regions of the normal swine brain were not associated with any obvious histological or morphological change, sign of microglial activation or demyelination phenomena, which are processes more frequently observed at a later stage during the progression of the post-radiation process especially following higher cumulative doses (> 6 months/years post-radiation) 45 . Moreover, our findings show that the neuroanatomical regions involved in this radiation-induced protein level reduction are not uniformly altered along the same trajectory across the different regions of the brain analyzed in this study.…”

Proceedings of the 2019 National Toxicology Program Satellite Symposium

“…107 Similar microvascular lesions have been observed in the brains of rhesus monkeys receiving 40 gray of fractionated whole-brain irradiation. 112,113 Some authors have argued that vascular injury in the retina may coincide with or predict cerebrovascular injury, underlining the utility of fundoscopy as a screening tool. 114…”

Reduction of pTau and APP Levels in Mammalian Brain After Low-Dose Radiation

“…Importantly, these ndings on early molecular changes in a normal (non-transgenic) large mammalian brain in the absence of obvious neurohistological changes or brain lesions support the hypothesis that early speci c molecular changes occur and are detectable after 4 weeks post-radiation across different brain regions exposed to the same fractionated low-dose of total-body radiation. Remarkably, the lower levels of pTau, APP and GAP43 observed across the different examined regions of the swine brain were not associated with apparent histological or morphological changes or activation signs of microglial cells or demyelination phenomena, which are two processes normally observed at a later stage during the progression of the post-radiation process (>6 months/years after post-radiation) 33 . In addition, these novel ndings show that the neuroanatomical regions involved in radiation-induced reduction of the examined protein expression levels are not uniformly altered along the same direction across different regions of the brain.…”

“…4 weeks) could greatly help in elucidating some of the earlier molecular events associated with different types of late neurological sequelae. These sequelae, among others, include neuroin ammatory and demyelination phenomena, which are often observed during the later phases of the post-radiation natural progression in those subjects exposed to brain radiation for either medical or non-medical reasons 33,34 . Moreover, a better understanding of the post-radiation molecular and neuropathological changes in normal large mammalian brain tissue could also considerably contribute to identifying more effective prophylactic options that could be used in either clinical or nuclear environmental contamination/attack settings.…”