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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

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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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References

  1. Graus F, Walker RW, Allen JC. Brain metastases in children. J Pediatr. 1983;103:558–61.

    Article  CAS  PubMed  Google Scholar 

  2. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep. 2012;14:48–54.

    Article  PubMed  Google Scholar 

  3. Gaspar LE, et al. The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2010;96:17–32.

    Article  PubMed  Google Scholar 

  4. Patil CG, et al. Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Cochrane Database Syst Rev. 2017;9:CD006121.

    PubMed  Google Scholar 

  5. Tsao MN, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2018. https://doi.org/10.1002/14651858.CD003869.pub4.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Park K, et al. Radiotherapy for brain metastasis and long-term survival. Sci Rep. 2021;11:8046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee YW, Cho HJ, Lee WH, Sonntag WE. Whole brain radiation-induced cognitive impairment: pathophysiological mechanisms and therapeutic targets. Biomol Ther. 2012;20:357–70.

    Article  CAS  Google Scholar 

  8. Dieckmann K, Herrmann H. Are there still indications for whole brain irradiation in 2021? Memo - Mag Eur Med Oncol. 2021;14:204–7.

    Google Scholar 

  9. van Grinsven EE, Nagtegaal SHJ, Verhoeff JJC, van Zandvoort MJE. The impact of stereotactic or whole brain radiotherapy on neurocognitive functioning in adult patients with brain metastases: a systematic review and meta-analysis. Oncol Res Treat. 2021;44:622–36.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Khuntia D, Brown P, Li J, Mehta MP. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol. 2006;24:1295–304.

    Article  CAS  PubMed  Google Scholar 

  11. Welzel G, et al. Acute neurocognitive impairment during cranial radiation therapy in patients with intracranial tumors. Strahlenther Onkol. 2008;184:647.

    Article  PubMed  Google Scholar 

  12. Welzel G, et al. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys. 2008;72:1311–8.

    Article  PubMed  Google Scholar 

  13. Brown PD, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA. 2016;316:401–9.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Meyers CA, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22:157–65.

    Article  CAS  Google Scholar 

  15. Greene-Schloesser D, et al. Radiation-induced brain injury: a review. Front Oncol. 2012;2:73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yabluchanskiy A, et al. Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation-induced impairment of neurovascular coupling responses protecting cognitive function in mice. GeroScience. 2020;42:409–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lamproglou I, et al. Total body 4.5 Gy gamma irradiation-induced early delayed learning and memory dysfunction in the rat. Cell Mol Biol Noisy Gd Fr. 2001;47:453–7.

    CAS  Google Scholar 

  18. Shi L, et al. Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus. Radiat Res. 2006;166:892–9.

    Article  CAS  PubMed  Google Scholar 

  19. Soussain C, et al. CNS complications of radiotherapy and chemotherapy. The Lancet. 2009;374:1639–51.

    Article  CAS  Google Scholar 

  20. Warrington JP, Csiszar A, Mitschelen M, Lee YW, Sonntag WE. Whole brain radiation-induced impairments in learning and memory are time-sensitive and reversible by systemic hypoxia. PLoS ONE. 2012;7:e30444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ungvari Z, et al. Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. GeroScience. 2017;39:33–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Robbins ME, Bourland JD, Cline JM, Wheeler KT, Deadwyler SA. A model for assessing cognitive impairment after fractionated whole-brain irradiation in nonhuman primates. Radiat Res. 2011;175:519–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hanbury DB, et al. Pathology of fractionated whole-brain irradiation in rhesus monkeys ( Macaca mulatta ). Radiat Res. 2015;183:367–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brown WR, Thore CR, Moody DM, Robbins ME, Wheeler KT. Vascular damage after fractionated whole-brain irradiation in rats. Radiat Res. 2005;164:662–8.

    Article  CAS  PubMed  Google Scholar 

  25. Shi L, et al. Maintenance of white matter integrity in a rat model of radiation-induced cognitive impairment. J Neurol Sci. 2009;285:178–84.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Connor M, et al. Regional susceptibility to dose-dependent white matter damage after brain radiotherapy. Radiother Oncol. 2017;123:209–17.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron. 2017;96:17–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ashpole NM, et al. Systemic influences contribute to prolonged microvascular rarefaction after brain irradiation: a role for endothelial progenitor cells. Am J Physio - Heart Circ Physiol. 2014;307:H858–68.

    Article  CAS  Google Scholar 

  29. Lee WH, Cho HJ, Sonntag WE, Lee YW. Radiation attenuates physiological angiogenesis by differential expression of VEGF, Ang-1, tie-2 and Ang-2 in rat brain. Radiat Res. 2011;176:753–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Warrington JP, et al. Whole brain radiation-induced vascular cognitive impairment: mechanisms and implications. J Vasc Res. 2013;50:445–57.

    Article  PubMed  Google Scholar 

  31. Warrington JP, et al. Cerebral microvascular rarefaction induced by whole brain radiation is reversible by systemic hypoxia in mice. Am. J. Physiol.-Heart Circ. Physiol. 2011;300:H736–44.

    CAS  Google Scholar 

  32. Correa DD, et al. Longitudinal cognitive assessment in patients with primary CNS lymphoma treated with induction chemotherapy followed by reduced-dose whole-brain radiotherapy or autologous stem cell transplantation. J Neurooncol. 2019;144:553–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Stokes TB, et al. White matter changes in breast cancer brain metastases patients who undergo radiosurgery alone compared to whole brain radiation therapy plus radiosurgery. J Neurooncol. 2015;121:583–90.

    Article  CAS  PubMed  Google Scholar 

  34. Cheng H, Chen H, Lv Y, Chen Z, Li CR. Prospective memory impairment following whole brain radiotherapy in patients with metastatic brain cancer. Cancer Med. 2018;7:5315–21.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bovi JA, et al. Pretreatment volume of MRI-determined white matter injury predicts neurocognitive decline after hippocampal avoidant whole-brain radiation therapy for brain metastases: secondary analysis of NRG Oncology Radiation Therapy Oncology Group 0933. Adv Radiat Oncol. 2019;4:579–86.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Mayinger M, et al. Leukoencephalopathy after prophylactic whole-brain irradiation with or without hippocampal sparing: a longitudinal magnetic resonance imaging analysis. Eur J Cancer. 2020;124:194–203.

    Article  CAS  PubMed  Google Scholar 

  37. Yoo DH, et al. MR imaging evaluation of intracerebral hemorrhages and T2 hyperintense white matter lesions appearing after radiation therapy in adult patients with primary brain tumors. PLoS ONE. 2015;10:e0136795.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Andrews RN, et al. White matter is the predilection site of late-delayed radiation-induced brain injury in non-human primates. Radiat Res. 2019;191:217–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Panagiotakos G, et al. Long-term impact of radiation on the stem cell and oligodendrocyte precursors in the brain. PLoS ONE. 2007;2:e588.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Li B, Ohtomo R, Thunemann M, Adams SR, Yang J, Fu B, Yaseen MA, et al. Two-photon microscopic imaging of capillary red blood cell flux in mouse brain reveals vulnerability of cerebral white matter to hypoperfusion. J Cereb Blood Flow Metab. 2020;40(12):501–12. https://doi.org/10.1177/0271678X19831016.

  41. Ahn SJ, et al. Label-free assessment of hemodynamics in individual cortical brain vessels using third harmonic generation microscopy. Biomed Opt Express. 2020;11:2665–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Esipova TV, et al. Oxyphor 2P: A high-performance probe for deep-tissue longitudinal oxygen imaging. Cell Metab. 2019;29:736-744.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li B, et al. More homogeneous capillary flow and oxygenation in deeper cortical layers correlate with increased oxygen extraction. ELife. 2019;8:e42299.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Demaria M, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014;31:722–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Goldey GJ, et al. Removable cranial windows for long-term imaging in awake mice. Nat Protoc. 2014;9:2515–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Komiyama T, et al. Learning-related fine-scale specificity imaged in motor cortex circuits of behaving mice. Nature. 2010;464:1182–6.

    Article  CAS  PubMed  Google Scholar 

  47. Sakadžić S, et al. Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue. Nat Methods. 2010;7:755–9.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Yaseen MA, et al. Multimodal optical imaging system for in vivo investigation of cerebral oxygen delivery and energy metabolism. Biomed Opt Express. 2015;6:4994–5007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Unekawa M, et al. RBC velocities in single capillaries of mouse and rat brains are the same, despite 10-fold difference in body size. Brain Res. 2010;1320:69–73.

    Article  CAS  PubMed  Google Scholar 

  50. Li B, Lee J, Boas DA, Lesage F. Contribution of low- and high-flux capillaries to slow hemodynamic fluctuations in the cerebral cortex of mice. J Cereb Blood Flow Metab. 2016;36(8):1351–6. https://doi.org/10.1177/0271678X16649195.

  51. Lee J, Wu W, Lesage F, Boas DA. Multiple-capillary measurement of RBC speed, flux, and density with optical coherence tomography. J. Cereb. Blood Flow Metab. Off J Int Soc Cereb Blood Flow Metab. 2013;33:1707–10.

    Article  Google Scholar 

  52. Srinivasan VJ, et al. Quantitative cerebral blood flow with optical coherence tomography. Opt Express. 2010;18:2477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Finikova OS, et al. Oxygen microscopy by two-photon-excited phosphorescence. ChemPhysChem. 2008;9:1673–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Uchida K, Reilly MP, Asakura T. Molecular stability and function of mouse hemoglobins. Zoolog Sci. 1998;15:703–6.

    Article  CAS  Google Scholar 

  55. Lecoq J, et al. Simultaneous two-photon imaging of oxygen and blood flow in deep cerebral vessels. Nat Med. 2011;17:893–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Parpaleix A, Houssen YG, Charpak S. Imaging local neuronal activity by monitoring PO2 transients in capillaries. Nat Med. 2013;19:241–6.

    Article  CAS  PubMed  Google Scholar 

  57. Tahir W, Kura S, Zhu J, Cheng X, Damseh R, Tadesse F, et al. Anatomical modeling of brain vasculature in two-photon microscopy by generalizable deep learning. BME Frontiers. 2020. https://doi.org/10.34133/2020/8620932.

  58. Damseh R, Delafontaine-Martel P, Pouliot P, Cheriet F, Lesage F. Laplacian flow dynamics on geometric graphs for anatomical modeling of cerebrovascular networks. IEEE Trans Med Imaging. 2021;40:381–94.

    Article  PubMed  Google Scholar 

  59. Gui C, et al. A prospective evaluation of whole brain volume loss and neurocognitive decline following hippocampal-sparing prophylactic cranial irradiation for limited-stage small-cell lung cancer. J Neurooncol. 2019;144:351–8.

    Article  CAS  PubMed  Google Scholar 

  60. Takeshita Y, et al. Early volume reduction of the hippocampus after whole-brain radiation therapy: an automated brain structure segmentation study. Jpn J Radiol. 2020;38:118–25.

    Article  PubMed  Google Scholar 

  61. Shibamoto Y, et al. Incidence of brain atrophy and decline in Mini-Mental State Examination score after whole-brain radiotherapy in patients with brain metastases: a prospective Study. Int J Radiat Oncol. 2008;72:1168–73.

    Article  Google Scholar 

  62. Lyons DG, Parpaleix A, Roche M, Charpak S. Mapping oxygen concentration in the awake mouse brain. ELife. 2016;5:e12024.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Moeini M, et al. Compromised microvascular oxygen delivery increases brain tissue vulnerability with age. Sci Rep. 2018;8:8219.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Blinder P, et al. The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. Nat Neurosci. 2013;16:889–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ballabh P, Braun A, Nedergaard M. Anatomic analysis of blood vessels in germinal matrix, cerebral cortex, and white matter in developing infants. Pediatr Res. 2004;56:117–24.

    Article  PubMed  Google Scholar 

  66. Cavaglia M, et al. Regional variation in brain capillary density and vascular response to ischemia. Brain Res. 2001;910:81–93.

    Article  CAS  PubMed  Google Scholar 

  67. Müller K, Courtois G, Ursini MV, Schwaninger M. New insight into the pathogenesis of cerebral small-vessel diseases. Stroke. 2017;48:520–7.

    Article  PubMed  Google Scholar 

  68. Chojdak-Łukasiewicz J, Dziadkowiak E, Zimny A, Paradowski B. Cerebral small vessel disease: a review. Adv. Clin. Exp Med Off Organ Wroclaw Med Univ. 2021;30:349–56.

    Google Scholar 

  69. Pantoni L, Poggesi A, Inzitari D. The relation between white-matter lesions and cognition. Curr Opin Neurol. 2007;20:390–7.

    Article  PubMed  Google Scholar 

  70. Horsfield MA, Jones DK. Applications of diffusion-weighted and diffusion tensor MRI to white matter diseases – a review. NMR Biomed. 2002;15:570–7.

    Article  PubMed  Google Scholar 

  71. Nakao S, Yamamoto T, Kimura S, Mino T, Iwamoto T. Brain white matter lesions and postoperative cognitive dysfunction: a review. J Anesth. 2019;33:336–40.

    Article  PubMed  Google Scholar 

  72. Golub AS, Pittman RN. Erythrocyte-associated transients in PO2 revealed in capillaries of rat mesentery. Am J Physiol Heart Circ Physiol. 2005;288:H2735-2743.

    Article  CAS  PubMed  Google Scholar 

  73. Cabrales P, Intaglietta M. Time-dependant oxygen partial pressure in capillaries and tissue in the hamster window chamber model. Antioxid Redox Signal. 2007;9:845–53.

    Article  CAS  PubMed  Google Scholar 

  74. Barker MC, Golub AS, Pittman RN. Erythrocyte-associated transients in capillary PO2: an isovolemic hemodilution study in the rat spinotrapezius muscle. Am J Physiol Heart Circ Physiol. 2007;292:H2540-2549.

    Article  CAS  PubMed  Google Scholar 

  75. Wälchli T, et al. Hierarchical imaging and computational analysis of three-dimensional vascular network architecture in the entire postnatal and adult mouse brain. Nat Protoc. 2021;16:4564–610.

    Article  PubMed  Google Scholar 

  76. Akiyama K, Tanaka R, Sato M, Takeda N. Cognitive dysfunction and histological findings in adult rats one year after whole brain irradiation. Neurol Med Chir (Tokyo). 2001;41:590–8.

    Article  CAS  PubMed  Google Scholar 

  77. Nakagaki H, Brunhart G, Kemper TL, Caveness WF. Monkey brain damage from radiation in the therapeutic range. J Neurosurg. 1976;44:3–11.

    Article  CAS  PubMed  Google Scholar 

  78. Andrews RN, et al. Cerebrovascular remodeling and neuroinflammation is a late effect of radiation-induced brain injury in non-human primates. Radiat Res. 2017;187:599–611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Constanzo J, et al. Diffusion MRI monitoring of specific structures in the irradiated rat brain. Magn Reson Med. 2018;80:1614–25.

    Article  PubMed  Google Scholar 

  80. Peiffer AM, Shi L, Olson J, Brunso-Bechtold JK. Differential effects of radiation and age on diffusion tensor imaging in rats. Brain Res. 2010;1351:23–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Correa DD, et al. Cognitive functions in survivors of primary central nervous system lymphoma. Neurology. 2004;62:548–55.

    Article  CAS  PubMed  Google Scholar 

  82. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989;39:789–96.

    Article  CAS  PubMed  Google Scholar 

  83. Duan F, et al. Whole-brain changes in white matter microstructure after radiotherapy for nasopharyngeal carcinoma: a diffusion tensor imaging study. Eur. Arch. Oto-Rhino-Laryngol. Off. J. Eur. Fed. Oto-Rhino-Laryngol. Soc. EUFOS Affil. Ger Soc Oto-Rhino-Laryngol - Head Neck Surg. 2016;273:4453–9.

    Google Scholar 

  84. Frytak S, et al. Magnetic resonance imaging for neurotoxicity in long-term survivors of carcinoma. Mayo Clin Proc. 1985;60:803–12.

    Article  CAS  PubMed  Google Scholar 

  85. King TZ, Wang L, Mao H. Disruption of white matter integrity in adult survivors of childhood brain tumors: correlates with long-term intellectual outcomes. PLoS ONE. 2015;10:e0131744.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Conill C, et al. Incidence of radiation-induced leukoencephalopathy after whole brain radiotherapy in patients with brain metastases. Clin Transl Oncol. 2007;9:590–5.

    Article  CAS  PubMed  Google Scholar 

  87. Bompaire F, et al. New insights in radiation-induced leukoencephalopathy: a prospective cross-sectional study. Support. Care Cancer Off. J Multinatl Assoc Support Care Cancer. 2018;26:4217–26.

    Article  Google Scholar 

  88. Rubinstein LJ, Herman MM, Long TF, Wilbur JR. Disseminated necrotizing leukoencephalopathy: a complication of treated central nervous system leukemia and lymphoma. Cancer. 1975;35:291–305.

    Article  CAS  PubMed  Google Scholar 

  89. Lee JS, et al. Neurotoxicity in long-term survivors of small cell lung cancer. Int J Radiat Oncol Biol Phys. 1986;12:313–21.

    Article  CAS  PubMed  Google Scholar 

  90. Lee YY, Nauert C, Glass JP. Treatment-related white matter changes in cancer patients. Cancer. 1986;57:1473–82.

    Article  CAS  PubMed  Google Scholar 

  91. Leng X, et al. Application of a machine learning method to whole brain white matter injury after radiotherapy for nasopharyngeal carcinoma. Cancer Imaging Off. Publ Int Cancer Imaging Soc. 2019;19:19.

    Article  Google Scholar 

  92. Monaco EA, et al. Leukoencephalopathy after whole-brain radiation therapy plus radiosurgery versus radiosurgery alone for metastatic lung cancer. Cancer. 2013;119:226–32.

    Article  PubMed  Google Scholar 

  93. Schuitema I, et al. Accelerated aging, decreased white matter integrity, and associated neuropsychological dysfunction 25 years after pediatric lymphoid malignancies. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31:3378–88.

    Article  Google Scholar 

  94. Szerlip N, et al. Factors impacting volumetric white matter changes following whole brain radiation therapy. J Neurooncol. 2011;103:111–9.

    Article  PubMed  Google Scholar 

  95. Vigliani MC, et al. Dementia following treatment of brain tumors with radiotherapy administered alone or in combination with nitrosourea-based chemotherapy: a clinical and pathological study. J Neurooncol. 1999;41:137–49.

    Article  CAS  PubMed  Google Scholar 

  96. Wang S, et al. Longitudinal diffusion tensor magnetic resonance imaging study of radiation-induced white matter damage in a rat model. Cancer Res. 2009;69:1190–8.

    Article  CAS  PubMed  Google Scholar 

  97. Moretti R, Caruso P. An iatrogenic model of brain small-vessel disease: post-radiation encephalopathy. Int J Mol Sci. 2020;21:6506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hattori H, Takeda M, Kudo T, Nishimura T, Hashimoto S. Cumulative white matter changes in the gerbil brain under chronic cerebral hypoperfusion. Acta Neuropathol (Berl). 1992;84:437–42.

    Article  CAS  PubMed  Google Scholar 

  99. Dalby RB, Eskildsen SF, Videbech P, Frandsen J, Mouridsen K, Sørensen L, et al. Oxygenation differs among white matter hyperintensities, intersected fiber tracts and unaffected white matter. Brain Commun. 1(1):fcz033. https://doi.org/10.1093/braincomms/fcz033.

  100. Brown WR, Moody DM, Thore CR, Challa VR, Anstrom JA. Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well. J Neurol Sci. 2007;257:62–6.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Joutel A, et al. Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J Clin Invest. 2010;120:433–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Miura M, et al. High prevalence of small vessel disease long after cranial irradiation. J Clin Neurosci Off J Neurosurg Soc Australas. 2017;46:129–35.

    Google Scholar 

  103. Lo EH, Frankel KA, Steinberg GK, DeLaPaz RL, Fabrikant JI. High-dose single-fraction brain irradiation: MRI, cerebral blood flow, electrophysiological, and histological studies. Int J Radiat Oncol Biol Phys. 1992;22:47–55.

    Article  CAS  PubMed  Google Scholar 

  104. Remler MP, Marcussen WH, Tiller-Borsich J. The late effects of radiation on the blood brain barrier. Int J Radiat Oncol Biol Phys. 1986;12:1965–9.

    Article  CAS  PubMed  Google Scholar 

  105. Nakata H, et al. Early blood-brain barrier disruption after high-dose single-fraction irradiation in rats. Acta Neurochir (Wien). 1995;136:82–6 (discussion 86-87).

    Article  CAS  PubMed  Google Scholar 

  106. Yoshida Y, et al. X-ray irradiation induces disruption of the blood-brain barrier with localized changes in claudin-5 and activation of microglia in the mouse brain. Neurochem Int. 2018;119:199–206.

    Article  CAS  PubMed  Google Scholar 

  107. Yuan H, Gaber MW, Boyd K, Wilson CM, Kiani MF, Merchant TE. Effects of fractionated radiation on the brain vasculature in a murine model: blood-brain barrier permeability, astrocyte proliferation, and ultrastructural changes. Int J Radiat Oncol Biol. Phys. 2006;66(3):860–6. https://doi.org/10.1016/j.ijrobp.2006.06.043.

  108. Balasubramanian P, et al. Obesity-induced cognitive impairment in older adults: a microvascular perspective. Am J Physiol Heart Circ Physiol. 2021;320:H740–61.

    Article  CAS  PubMed  Google Scholar 

  109. Ungvari Z, et al. Hypertension-induced cognitive impairment: from pathophysiology to public health. Nat Rev Nephrol. 2021;17:639–54.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Toth P, et al. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J. Cereb. Blood Flow Metab. Off J Int Soc Cereb Blood Flow Metab. 2013;33:1732–42.

    Article  CAS  Google Scholar 

  111. Tucsek Z, et al. Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci. 2014;69:1339–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Fu Z, et al. Age-dependent responses of brain myelin integrity and behavioral performance to radiation in mice. Radiat Res. 2017;188:505–16.

    Article  CAS  PubMed  Google Scholar 

  113. Li J, Xiao L, He D, Luo Y, Sun H. Mechanism of white matter injury and promising therapeutic strategies of MSCs after intracerebral hemorrhage. Front Aging Neurosci. 2021;13:632054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hung P-L, Huang C-C, Huang H-M, Tu D-G, Chang Y-C. Thyroxin treatment protects against white matter injury in the immature brain via brain-derived neurotrophic factor. Stroke. 2013;44:2275–83.

    Article  CAS  PubMed  Google Scholar 

  115. Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell. 2005;8:89–91.

    Article  CAS  PubMed  Google Scholar 

  116. Furuse M, Nonoguchi N, Kawabata S, Miyatake S-I, Kuroiwa T. Delayed brain radiation necrosis: pathological review and new molecular targets for treatment. Med Mol Morphol. 2015;48:183–90.

    Article  CAS  PubMed  Google Scholar 

  117. Abayomi OK. Pathogenesis of irradiation-induced cognitive dysfunction. Acta Oncol. 1996;35:659–63.

    Article  CAS  PubMed  Google Scholar 

  118. Ungvari Z, et al. Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitivity. J Gerontol Ser A. 2013;68:1443–57.

    Article  CAS  Google Scholar 

  119. Imaizumi N, Monnier Y, Hegi M, Mirimanoff R-O, Rüegg C. Radiotherapy suppresses angiogenesis in mice through TGF-betaRI/ALK5-dependent inhibition of endothelial cell sprouting. PLoS ONE. 2010;5:e11084.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Robbins MEC, Zhao W. Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int J Radiat Biol. 2004;80:251–9.

    Article  CAS  PubMed  Google Scholar 

  121. Greene-Schloesser D, Moore E, Robbins ME. Molecular pathways: radiation-induced cognitive impairment. Clin. Cancer Res. Off J Am Assoc Cancer Res. 2013;19:2294–300.

    Article  CAS  Google Scholar 

  122. Fleckenstein K, et al. Temporal onset of hypoxia and oxidative stress after pulmonary irradiation. Int J Radiat Oncol. 2007;68:196–204.

    Article  CAS  Google Scholar 

  123. Todorović A, Kasapović J, Pejić S, Stojiljković V, Pajović SB. Differences in antioxidative response of rat hippocampus and cortex after exposure to clinical dose of gamma-rays. Ann N Y Acad Sci. 2005;1048:369–72.

    Article  PubMed  Google Scholar 

  124. Smith KJ, Kapoor R, Felts PA. Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol Zurich Switz. 1999;9:69–92.

    Article  CAS  Google Scholar 

  125. Peuchen S, et al. Interrelationships between astrocyte function, oxidative stress and antioxidant status within the central nervous system. Prog Neurobiol. 1997;52:261–81.

    Article  CAS  PubMed  Google Scholar 

  126. Institoris A, et al. Whole brain irradiation in mice causes long-term impairment in astrocytic calcium signaling but preserves astrocyte-astrocyte coupling. GeroScience. 2021;43:197–212.

    Article  CAS  PubMed  Google Scholar 

  127. Srinivasan VJ, Mandeville ET, Can A, Blasi F, Climov M, Daneshmand A, et al. Multiparametric, longitudinal optical coherence tomography imaging reveals acute injury and chronic recovery in experimental ischemic stroke. PLoS One. 2013;8(8):e71478. https://doi.org/10.1371/journal.pone.0071478.

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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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Author notes

  1. Baoqiang Li and Andriy Yabluchanskiy contributed equally to this study.

Authors and Affiliations

  1. Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, Guangdong, China

    Baoqiang Li & Ji Leng

  2. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA

    Baoqiang Li, Ikbal Şencan-Eğilmez, Mohammed Ali H. Alfadhel, Jason E. Porter, Buyin Fu, Chongzhao Ran & Sava Sakadžić

  3. Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Andriy Yabluchanskiy, Stefano Tarantini, William E. Sonntag, Anna Csiszar & Zoltan Ungvari

  4. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Andriy Yabluchanskiy, Stefano Tarantini & Zoltan Ungvari

  5. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Andriy Yabluchanskiy, Stefano Tarantini, William E. Sonntag, Anna Csiszar & Zoltan Ungvari

  6. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, 1083, Hungary

    Stefano Tarantini & Zoltan Ungvari

  7. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Srinivasa Rao Allu & Sergei A. Vinogradov

  8. Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Srinivasa Rao Allu & Sergei A. Vinogradov

  9. Biophotonics Research Center, Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Ikbal Şencan-Eğilmez

  10. Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA

    Sefik Evren Erdener & David A. Boas

  11. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, 1083, Hungary

    Anna Csiszar

Authors
  1. Baoqiang Li
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  2. Andriy Yabluchanskiy
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Contributions

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.

Corresponding authors

Correspondence to Zoltan Ungvari or Sava Sakadžić.

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Disclaimer

The funding sources had no role in the study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the American Heart Association, or the Presbyterian Health Foundation.

Conflict of interest

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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