title: Capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: a potential rat model of vascular dementia.
abstract: Brain tumor patients who are long-term survivors after whole-brain irradiation (WBI) often suffer cognitive impairment, including dementia. Although the pathogenic mechanisms remain poorly understood, our studies suggest that radiation-induced cognitive impairment may be a form of vascular dementia. We used a fractionated dose of gamma-rays that is biologically similar to that given to brain tumor patients. The brains of adult rats were irradiated with 40 Gy, in eight 5 Gy fractions over 4 weeks. Cognitive function was assessed prior to WBI and up to 9 months post-irradiation using a partially-baited radial arm maze. A significant increase in working memory errors was found in the irradiated rats by two-way ANOVA (p=0.0042). The increased errors occurred primarily at 6 and 9 months (p < 0.05, student's t-test). Vessel density was quantified using a stereology method with computerized image processing and analysis. Vessel density was unchanged 24 h after the last dose, but significantly decreased (p=0.002), by approximately 30%, from 10 weeks to 52 weeks. Thus, cognitive impairment arose after brain capillary loss in irradiated rats that show no other gross brain pathology. Capillary loss may play an important role in radiation-induced dementia and this may be a model of vascular dementia.
authors.affiliation: Department of Radiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. wibrown@wfubmc.edu
authors.forename: William R
authors.initials: WR
authors.lastname: Brown
authors.forename: Robert M
authors.initials: RM
authors.lastname: Blair
authors.forename: Dixon M
authors.initials: DM
authors.lastname: Moody
authors.forename: Clara R
authors.initials: CR
authors.lastname: Thore
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ahmed
authors.forename: Michael E
authors.initials: ME
authors.lastname: Robbins
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Wheeler
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D001932:Brain Neoplasms / Q000532:radiotherapy; D002196:Capillaries / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects*; D002536:Cerebral Arteries / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects*; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D015140:Dementia, Vascular / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D019583:Dose Fractionation, Radiation; D018782:Maze Learning / Q000528:radiation effects; D011832:Radiation Injuries / Q000473:pathology* / Q000503:physiopathology; D011878:Radiotherapy / Q000009:adverse effects*; D051381:Rats; D011916:Rats, Inbred F344; D012307:Risk Factors; D013995:Time