title: Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates.
abstract: Fractionated whole-brain irradiation (fWBI) is a mainstay of treatment for patients with intracranial neoplasia; however late-delayed radiation-induced normal tissue injury remains a major adverse consequence of treatment, with deleterious effects on quality of life for affected patients. We hypothesize that cerebrovascular injury and remodeling after fWBI results in ischemic injury to dependent white matter, which contributes to the observed cognitive dysfunction. To evaluate molecular effectors of radiation-induced brain injury (RIBI), real-time quantitative polymerase chain reaction (RT-qPCR) was performed on the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46), hippocampus and temporal white matter of 4 male Rhesus macaques (age 6-11 years), which had received 40 Gray (Gy) fWBI (8 fractions of 5 Gy each, twice per week), and 3 control comparators. All fWBI animals developed neurologic impairment; humane euthanasia was elected at a median of 6 months. Radiation-induced brain injury was confirmed histopathologically in all animals, characterized by white matter degeneration and necrosis, and multifocal cerebrovascular injury consisting of perivascular edema, abnormal angiogenesis and perivascular extracellular matrix deposition. Herein we demonstrate that RIBI is associated with white matter-specific up-regulation of hypoxia-associated lactate dehydrogenase A (LDHA) and that increased gene expression of fibronectin 1 (FN1), SERPINE1 and matrix metalloprotease 2 (MMP2) may contribute to cerebrovascular remodeling in late-delayed RIBI. Additionally, vascular stability and maturation associated tumor necrosis super family member 15 (TNFSF15) and vascular endothelial growth factor beta (VEGFB) mRNAs were increased within temporal white matter. We also demonstrate that radiation-induced brain injury is associated with decreases in white matter-specific expression of neurotransmitter receptors SYP, GRIN2A and GRIA4. We additionally provide evidence that macrophage/microglial mediated neuroinflammation may contribute to RIBI through increased gene expression of the macrophage chemoattractant CCL2 and macrophage/microglia associated CD68. Global patterns in cerebral gene expression varied significantly between regions examined (P < 0.0001, Friedman's test), with effects most prominent within cerebral white matter.
authors.affiliation: a   Department of Pathology, Section on Comparative Medicine; Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Andrews
authors.affiliation: b   Department of Radiation Oncology; Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.|c   Brain Tumor Center of Excellence; Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Metheny-Barlow
authors.affiliation: b   Department of Radiation Oncology; Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.|c   Brain Tumor Center of Excellence; Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Peiffer
authors.affiliation: f   Department of Psychology, Averett University, Danville, Virginia 24541.
authors.forename: David B
authors.initials: DB
authors.lastname: Hanbury
authors.affiliation: d   Department of Biostatistical Sciences; Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Tooze
authors.affiliation: b   Department of Radiation Oncology; Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.|c   Brain Tumor Center of Excellence; Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Bourland
authors.affiliation: e   Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hampson
authors.affiliation: e   Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Deadwyler
authors.affiliation: a   Department of Pathology, Section on Comparative Medicine; Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cline
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D002561:Cerebrovascular Disorders / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D016371:Cranial Irradiation / Q000009:adverse effects*; D004827:Epilepsy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000528:radiation effects; D011832:Radiation Injuries / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D011879:Radiotherapy Dosage; D066127:White Matter / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects
chemical_list: D009419:Nerve Tissue Proteins