GeroScience

, Volume 39, Issue 1, pp 33–42 | Cite as

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
  • Eszter Farkas
  • Anna Csiszar
  • Andriy Yabluchanskiy
Original Article

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.

Keywords

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

Notes

Acknowledgements

This work was supported by grants from the Reynolds Foundation (to AY), the American Heart Association (to ST, AC and ZU), the National Center for Complementary and Alternative Medicine (R01-AT006526), the National Institute on Aging (R01-AG047879; R01-AG038747; 3P30AG050911-02S1), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218), the Oklahoma Center for the Advancement of Science and Technology (to AY, AC, ZU) and the IBEST-OUHSC (to AY).

Compliance with ethical standards

Disclosure

None.

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Copyright information

© American Aging Association 2017

Authors and Affiliations

  • Zoltan Ungvari
    • 1
    • 2
    • 3
  • Stefano Tarantini
    • 1
    • 2
  • Peter Hertelendy
    • 1
    • 3
  • M. Noa Valcarcel-Ares
    • 1
    • 2
  • Gabor A. Fülöp
    • 1
    • 2
  • Sreemathi Logan
    • 1
  • Tamas Kiss
    • 1
    • 2
  • Eszter Farkas
    • 2
    • 3
  • Anna Csiszar
    • 1
    • 2
    • 3
  • Andriy Yabluchanskiy
    • 1
    • 2
  1. 1.Reynolds Oklahoma Center on Aging, Department of Geriatric MedicineUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric MedicineUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  3. 3.Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and InformaticsUniversity of SzegedSzegedHungary

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