Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence

Zoltan Ungvari, Stefano Tarantini, Peter Hertelendy, M. Noa Valcarcel-Ares, Gabor A. Fülöp, Sreemathi Logan, Tamas Kiss, E. Farkas, Anna Csiszar, Andriy Yabluchanskiy

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)33-42
Number of pages10
JournalGeroScience
Volume39
Issue number1
DOIs
Publication statusPublished - Feb 1 2017

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Gait
Cerebrovascular Circulation
Brain
Social Adjustment
Vibrissae
Laser-Doppler Flowmetry
Water
Hyperemia
Cognition
Cognitive Dysfunction
Dilatation
Neoplasms
Maintenance
Neoplasm Metastasis
Wounds and Injuries
Therapeutics

Keywords

  • Cellular senescence
  • Dementia
  • DNA damage
  • Functional hyperemia
  • Gait dysfunction
  • Neurovascular coupling
  • Neurovascular unit
  • Whole brain irradiation

ASJC Scopus subject areas

  • Ageing
  • Geriatrics and Gerontology

Cite this

Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. / Ungvari, Zoltan; Tarantini, Stefano; Hertelendy, Peter; Valcarcel-Ares, M. Noa; Fülöp, Gabor A.; Logan, Sreemathi; Kiss, Tamas; Farkas, E.; Csiszar, Anna; Yabluchanskiy, Andriy.

In: GeroScience, Vol. 39, No. 1, 01.02.2017, p. 33-42.

Research output: Contribution to journalArticle

Ungvari, Z, Tarantini, S, Hertelendy, P, Valcarcel-Ares, MN, Fülöp, GA, Logan, S, Kiss, T, Farkas, E, Csiszar, A & Yabluchanskiy, A 2017, 'Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence', GeroScience, vol. 39, no. 1, pp. 33-42. https://doi.org/10.1007/s11357-017-9964-z
Ungvari, Zoltan ; Tarantini, Stefano ; Hertelendy, Peter ; Valcarcel-Ares, M. Noa ; Fülöp, Gabor A. ; Logan, Sreemathi ; Kiss, Tamas ; Farkas, E. ; Csiszar, Anna ; Yabluchanskiy, Andriy. / Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. In: GeroScience. 2017 ; Vol. 39, No. 1. pp. 33-42.
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