Abstract
Whole-brain irradiation (WBI, also known as whole-brain radiation therapy) is a mainstay treatment modality for patients with multiple brain metastases. It is also used as a prophylactic treatment for microscopic tumors that cannot be detected by magnetic resonance imaging. WBI induces a progressive cognitive decline in ~ 50% of the patients surviving over 6 months, significantly compromising the quality of life. There is increasing preclinical evidence that radiation-induced injury to the cerebral microvasculature and accelerated neurovascular senescence plays a central role in this side effect of WBI. To better understand this side effect, male C57BL/6 mice were first subjected to a clinically relevant protocol of fractionated WBI (5 Gy, two doses per week, for 4 weeks). Nine months post the WBI treatment, we applied two-photon microscopy and Doppler optical coherence tomography to measure capillary red-blood-cell (RBC) flux, capillary morphology, and microvascular oxygen partial pressure (PO2) in the cerebral somatosensory cortex in the awake, head-restrained, WPI-treated mice and their age-matched controls, through a cover-glass-sealed chronic cranial window. Thanks to the extended penetration depth with the fluorophore — Alexa680, measurements of capillary blood flow properties (e.g., RBC flux, speed, and linear density) in the cerebral subcortical white matter were enabled. We found that the WBI-treated mice exhibited a significantly decreased capillary RBC flux in the white matter. WBI also caused a significant reduction in capillary diameter, as well as a large (although insignificant) reduction in segment density at the deeper cortical layers (e.g., 600–700 μm), while the other morphological properties (e.g., segment length and tortuosity) were not obviously affected. In addition, we found that PO2 measured in the arterioles and venules, as well as the calculated oxygen saturation and oxygen extraction fraction, were not obviously affected by WBI. Lastly, WBI was associated with a significant increase in the erythrocyte-associated transients of PO2, while the changes of other cerebral capillary PO2 properties (e.g., capillary mean-PO2, RBC-PO2, and InterRBC-PO2) were not significant. Collectively, our findings support the notion that WBI results in persistent cerebral white matter microvascular impairment, which likely contributes to the WBI-induced brain injury and cognitive decline. Further studies are warranted to assess the WBI-induced changes in brain tissue oxygenation and malfunction of the white matter microvasculature as well.
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Acknowledgements
The authors thank Waleed Tahir and Lei Tian from Boston University, and Rafat Damseh and Frédéric Lesage from École Polytechnique de Montréal, Université de Montréal, for their technical supports on the microvascular morphological analysis.
Funding
This work was supported by the grants from the American Heart Association, the Oklahoma Center for the Advancement of Science and Technology, the National Institute on Aging (RF1AG072295, R01AG055395, R01AG068295, R01AG070915, and K01AG073614), the National Institute of Neurological Disorders and Stroke (R01NS100782, R01NS091230, R01NS115401, U19NS123717, and RF1NS121095), the National Cancer Center (R01CA255840), the National Institute of Biomedical Imaging and Bioengineering (U24EB028941), the National Heart, Lung, and Blood Institute (U01HL133362), the National Institute of Mental Health (R00MH120053), the Oklahoma Shared Clinical and Translational Resources (U54GM104938) with an Institutional Development Award (IDeA) from NIGMS, the Presbyterian Health Foundation, the Reynolds Foundation, the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), the Cellular and Molecular GeroScience CoBRE (P20GM125528), and the Science and Technology Innovation Committee of Shenzhen Municipality (JSGG20210420091601003).
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B.L., A.Y., S.S., and Z.U. designed the study; A.Y. prepared the WBI model with the guidance from S.U., S.T., W.E.S., and A.C.; B.L., I.S., and S.E.E. performed the experiments; B.L., J.E.P., M.A.H.A., and J.L. analyzed the data with the guidance from S.S.; B.L. and S.S. interpreted the results with the help from Z.U. and D.A.B.; S.V. developed the phosphorescence nanoprobe Oxyphor-2P and helped with the PO2 measurements; S.R.A. synthetized Oxyphor-2P with the guidance from S.V.; B.L. synthetized the dextran-Alexa680 dye with the guidance from C.R.; B.L. and Z.U. wrote the manuscript with help from S.S. and all other authors; S.S. and B.L. developed the imaging and data processing methods; B.F. performed the animal surgeries.
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Dr. Anna Csiszar serves as Associate Editor for the Journal of Gerontology, Series A: Biological Sciences and Medical Sciences and GeroScience. Dr. Andriy Yabluchanskiy serves as Guest Editor for the American Journal of Physiology-Heart and Circulatory Physiology. Dr. Zoltan Ungvari serves as Editor-in-Chief for GeroScience and as Consulting Editor for the American Journal of Physiology-Heart and Circulatory Physiology. The authors declare no other competing interests.
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Li, B., Yabluchanskiy, A., Tarantini, S. et al. Measurements of cerebral microvascular blood flow, oxygenation, and morphology in a mouse model of whole-brain irradiation-induced cognitive impairment by two-photon microscopy and optical coherence tomography: evidence for microvascular injury in the cerebral white matter. GeroScience 45, 1491–1510 (2023). https://doi.org/10.1007/s11357-023-00735-3
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DOI: https://doi.org/10.1007/s11357-023-00735-3