Pathology of Fractionated Whole-Brain Irradiation in Rhesus Monkeys (Macaca mulatta)

Abstract

Fractionated whole-brain irradiation (fWBI), used to treat brain metastases, often leads to neurologic injury and cognitive impairment. The cognitive effects of irradiation in nonhuman primates (NHP) have been previously published; this report focuses on corresponding neuropathologic changes that could have served as the basis for those effects in the same study. Four rhesus monkeys were exposed to 40 Gy of fWBI [5 Gy×8 fraction (fx), 2 fx/week for four weeks] and received anatomical MRI prior to, and 14 months after fWBI. Neurologic and histologic sequelae were studied posthumously. Three of the NHPs underwent cognitive assessments, and each exhibited radiation-induced impairment associated with various degrees of vascular and inflammatory neuropathology. Two NHPs had severe multifocal necrosis of the forebrain, midbrain and brainstem. Histologic and MRI findings were in agreement, and the severity of cognitive decrement previously reported corresponded to the degree of observed pathology in two of the animals. In response to fWBI, the NHPs showed pathology similar to humans exposed to radiation and show comparable cognitive decline. These results provide a basis for implementing NHPs to examine and treat adverse cognitive and neurophysiologic sequelae of radiation exposure in humans.

Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates

“…Furthermore, rodents do not develop white matter necrosis after fWBI (15, 16), as do humans. We and others (7, 17–19) have demonstrated that Rhesus macaques ( Macaca mulatta ) that receive fWBI (total dose of 40–80 Gy, 2–5 Gy per fraction) develop cerebrovascular and white matter lesions which are spatially, temporally and morphologically similar to those observed in humans with late-delayed RIBI (19). Furthermore, these irradiated animals developed progressive cognitive dysfunction (20), particularly at high cognitive workloads, and thus serve as a more human-like alternative to rodent models.…”

“…Housing, diet and experimental procedures are detailed in Hanbury et al . (19). Control comparators (n = 3, aged 5.5–6.6 years, 5.3–8.3 kg) had been part of an unrelated study in which they had received single dose, 10 Gy thoracic irradiation and subcutaneous injections of vehicle [1 mL SQ, sterile phosphorus-buffered saline(PBS)], twice daily for 4 months, ceasing 4 months prior to necropsy.…”

Relationship Between Radiation Dose and Microbleed Formation in Patients With Malignant Glioma

“…While the precise radiobiologic mechanism for this dose-latency effect has not been elucidated, we hypothesize that different mechanisms for CMB formation may be involved in low and high-dose regions. Specifically, direct endothelial damage on a relatively short time scale may dominate in high-dose regions, while indirect effects on vasculature with a longer latency period, including vascular proliferation, perivascular fibrosis and chronic microglial activation, may dominate in low-dose regions [9]. Further study of this doselatency effect is warranted.…”

“…Studies with primate [9] and murine models [10], as well as human autopsy studies [11,12], have demonstrated that microvascular damage is a prominent pathologic component of radiation-induced brain injury, with endothelial degeneration leading to the formation cerebral microbleeds (CMBs). CMBs have also been observed in elderly patients without known underlying pathology [13,14], as well as in other degenerative central nervous system conditions, including cerebral amyloid angiopathy (CAA) associated with Alzheimer's disease and vascular cognitive impairment [11], where they have been linked to cognitive dysfunction [15][16][17][18].…”

Long-Term Cognitive Functioning in Single-Dose Total-Body Gamma-Irradiated Rhesus Monkeys (Macaca mulatta)

“…In addition to cognitive changes due to normal aging (13), NHPs are excellent models of Alzheimer’s disease (14), Parkinson’s disease (15), depression (16), Huntington’s disease (17), schizophrenia (18, 19), as well as brain dysfunction related to ischemia (20), drug addiction (21), anxiety and emotional regulation (22). NHPs are also models for the study of radiation-induced brain pathology (9, 23, 24). Cognitive studies on the effects of single, sublethal radiation doses in NHPs have largely focused on early effects at very high (>11 Gy) doses (25, 26).…”