title: Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence.
abstract: Whole brain irradiation (WBI) is a mainstream therapy for patients with both identifiable brain metastases and prophylaxis for microscopic malignancies. However, it also promotes accelerated senescence in healthy tissues and leads to progressive cognitive dysfunction in up to 50% of tumor patients surviving long term after treatment, due to γ-irradiation-induced cerebromicrovascular injury. Moment-to-moment adjustment of cerebral blood flow (CBF) via neuronal activity-dependent cerebromicrovascular dilation (functional hyperemia) has a critical role in maintenance of healthy cognitive function. To determine whether cognitive decline induced by WBI associates with impaired cerebromicrovascular function, C56BL/6 mice (3 months) subjected to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks) and control mice were compared. Mice were tested for spatial memory performance (radial arm water maze), sensorimotor coordination (computerized gait analysis, CatWalk), and cerebromicrovascular function (whisker-stimulation-induced increases in CBF, measured by laser Doppler flowmetry) at 3 to 6 months post-irradiation. We found that mice with WBI exhibited impaired cerebromicrovascular function at 3 months post-irradiation, which was associated with impaired performance in the radial arm water maze. At 6 months, post-irradiation progressive impairment in gait coordination (including changes in the regularity index and phase dispersion) was also evident. Collectively, our findings provide evidence for early and persisting neurovascular impairment after a clinically relevant protocol of fractionated WBI, which predict early manifestations of cognitive impairment.
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.|Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.|Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tarantini
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.|Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Hertelendy
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.|Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: M Noa
authors.initials: MN
authors.lastname: Valcarcel-Ares
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.|Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Gabor A
authors.initials: GA
authors.lastname: Fülöp
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.
authors.forename: Sreemathi
authors.initials: S
authors.lastname: Logan
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.|Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Tamas
authors.initials: T
authors.lastname: Kiss
authors.affiliation: Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Farkas
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.|Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA. Andriy-Yabluchanskiy@ouhsc.edu.|Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Andriy-Yabluchanskiy@ouhsc.edu.
authors.forename: Andriy
authors.initials: A
authors.lastname: Yabluchanskiy
mesh_terms: D000818:Animals; D001921:Brain / Q000528:radiation effects*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D060825:Cognitive Dysfunction / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D019583:Dose Fractionation, Radiation; D007794:Lameness, Animal / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D000069336:Neurovascular Coupling; D011833:Radiation Injuries, Experimental / Q000150:complications*; D011897:Random Allocation; D012016:Reference Values; D013997:Time Factors
keywords: Cellular senescence; DNA damage; Dementia; Functional hyperemia; Gait dysfunction; Neurovascular coupling; Neurovascular unit; Whole brain irradiation