(D-153) Dimension-based Quantification of Aging-Associated Cerebral Microvasculature Determined by Optical Coherence Tomography Angiography and Two-Photon Microscopy

Introduction:: Aging is a major risk factor of human diseases and cerebral microvascular health is a key
biomarker to study natural aging and associated neurological diseases. Our aim is to study aging-associated
change of microvasculature and quantify the difference of cerebral blood vessels in mice from different age
groups, in vivo.

Materials and Methods:: We used optical coherence tomography (OCT) and two-photon microscopy (TPM) to obtain
< 18 months old and >18 months old C57BL/6J mice cerebral microvascular images in vivo through a chronic
cranial window (N=9 for OCT and TPM in nonaged group, N=14 for OCT and N=9 for TPM in aged group).
Mouse anatomy- and customize-based vascular dimension segmentations were employed to split vessels into
artery & vein, arteriole & venule, capillary, and specific size blood vessels for quantification assessments.

Results, Conclusions, and Discussions:: We found that artery & vein, arteriole & venule, and capillary from different age group showed significant
differences in density, length, diameter, complexity, perimeter, and tortuosity observed from both OCT
angiography (OCTA) and TPM imaging results. Particularly, OCTA and TPM provided the comprehensive
quantification for arteriole & venule via compensating the limitation of each modality alone in terms of
spatial resolution and imaging field of view (FOV). We further demonstrated that OCTA and TPM exhibited
a negative correlation in quantification analyses between nonaged and aged mice, which indicated that OCT
and TPM were able to offer effective vascular information to study the change of cerebral blood vessels in
aging. OCT and TPM can be used as multimodal imaging modalities to achieve in vivo vascular monitoring
and quantification for aging study in mouse brain through vascular quantification analyses.

Acknowledgements (Optional): : This work was supported by grants from the University of Oklahoma Health Sciences Center
(P30CA225520), Faculty Investment Program from University of Oklahoma, Institutional Research Grant
number IRG-19-142-01 from the American Cancer Society, National Science Foundation (OIA-2132161,
2238648), National Institute of Health (R01DK133717, R01CA255840), Oklahoma Shared Clinical and
Translational Resources (NIGMS U54GM104938), Oklahoma Center for the Advancement of Science and
Technology (HR23-071), and the medical imaging COBRE (P20 GM135009). Histology service provided
by the Tissue Pathology Shared Resource was supported in part by the National Institute of General Medical
Sciences COBRE Grant P20GM103639 and National Cancer Institute Grant P30CA225520 of the National
Institutes of Health. American Heart Association (ANT: AHA834339), the Oklahoma Center for the
Advancement of Science and Technology, the National Institute on Aging (RF1AG072295, R01AG055395,
R01AG068295; R01AG070915, K01AG073614), the National Institute of Neurological Disorders and
Stroke (R01NS100782).

References (Optional): : 1. T. Niccoli and L. Partridge, "Ageing as a risk factor for disease," Current biology 22, R741-R752 (2012).
2. R. Levy, "Aging-associated cognitive decline," International Psychogeriatrics 6, 63-68 (1994).
3. D. R. Riddle, W. E. Sonntag, and R. J. Lichtenwalner, "Microvascular plasticity in aging," Ageing research reviews 2, 149-
168 (2003).
4. E. Farkas and P. G. Luiten, "Cerebral microvascular pathology in aging and Alzheimer's disease," Progress in neurobiology
64, 575-611 (2001).
5. S. Laurent and P. Boutouyrie, "Arterial stiffness and hypertension in the elderly," Frontiers in cardiovascular medicine 7,
544302 (2020).
6. Z. Springo, P. Toth, S. Tarantini, N. M. Ashpole, Z. Tucsek, W. E. Sonntag, A. Csiszar, A. Koller, and Z. I. Ungvari, "Aging
impairs myogenic adaptation to pulsatile pressure in mouse cerebral arteries," Journal of Cerebral Blood Flow & Metabolism
35, 527-530 (2015).
7. Z. Chu, J. Lin, C. Gao, C. Xin, Q. Zhang, C.-L. Chen, L. Roisman, G. Gregori, P. J. Rosenfeld, and R. K. Wang, "Quantitative
assessment of the retinal microvasculature using optical coherence tomography angiography," Journal of biomedical optics
21, 066008-066008 (2016).
8. F. Cassot, F. Lauwers, C. Fouard, S. Prohaska, and V. Lauwers-Cances, "A novel three-dimensional computer-assisted
method for a quantitative study of microvascular networks of the human cerebral cortex," Microcirculation 13, 1-18 (2006).
9. W. R. Brown and C. R. Thore, "Cerebral microvascular pathology in ageing and neurodegeneration," Neuropathology and
applied neurobiology 37, 56-74 (2011).
10. B. Müller, S. Lang, M. Dominietto, M. Rudin, G. Schulz, H. Deyhle, M. Germann, F. Pfeiffer, C. David, and T. Weitkamp,
"High-resolution tomographic imaging of microvessels," in Developments in X-ray Tomography VI, (SPIE, 2008), 89-98.
11. W. D. Tucker, Y. Arora, and K. Mahajan, Anatomy, Blood Vessels (StatPearls Publishing, Treasure Island (FL), 2022).
12. Y. Muraoka, A. Tsujikawa, K. Kumagai, M. Akiba, K. Ogino, T. Murakami, Y. Akagi-Kurashige, K. Miyamoto, and N.
Yoshimura, "Age-and hypertension-dependent changes in retinal vessel diameter and wall thickness: an optical coherence
tomography study," American journal of ophthalmology 156, 706-714. e702 (2013).
13. B. A. Corliss, C. Mathews, R. Doty, G. Rohde, and S. M. Peirce, "Methods to label, image, and analyze the complex structural
architectures of microvascular networks," Microcirculation 26, e12520 (2019).
14. D. M. Moody, W. R. Brown, V. R. Challa, H. S. GHAZI‐BIRRY, and D. M. Reboussin, "Cerebral Microvascular Alterations
in Aging, Leukoaraiosis, and Alzheimer's Disease a," Annals of the New York Academy of Sciences 826, 103-116 (1997).
15. Y. Li, W. J. Choi, W. Wei, S. Song, Q. Zhang, J. Liu, and R. K. Wang, "Aging-associated changes in cerebral vasculature
and blood flow as determined by quantitative optical coherence tomography angiography," Neurobiology of aging 70, 148-
159 (2018).
16. C. R. Thore, J. A. Anstrom, D. M. Moody, V. R. Challa, M. C. Marion, and W. R. Brown, "Morphometric analysis of
arteriolar tortuosity in human cerebral white matter of preterm, young, and aged subjects," Journal of neuropathology and
experimental neurology 66, 337-345 (2007).
17. W. R. Brown, D. M. Moody, C. R. Thore, J. A. Anstrom, and V. R. Challa, "Microvascular changes in the white mater in
dementia," Journal of the neurological sciences 283, 28-31 (2009).
18. S. Ciurică, M. Lopez-Sublet, B. L. Loeys, I. Radhouani, N. Natarajan, M. Vikkula, A. H. Maas, D. Adlam, and A. Persu,
"Arterial tortuosity: novel implications for an old phenotype," Hypertension 73, 951-960 (2019).
19. E. Bullitt, G. Gerig, S. M. Pizer, W. Lin, and S. R. Aylward, "Measuring tortuosity of the intracerebral vasculature from
MRA images," IEEE transactions on medical imaging 22, 1163-1171 (2003).
20. Y. Yan, X. Zhou, Z. Chu, L. Stell, M. A. Shariati, R. K. Wang, and Y. J. Liao, "Vision loss in optic disc drusen correlates
with increased macular vessel diameter and flux and reduced peripapillary vascular density," American journal of
ophthalmology 218, 214-224 (2020).
21. Y. Zhang, H. Li, T. Cao, R. Chen, H. Qiu, Y. Gu, and P. Li, "Automatic 3D adaptive vessel segmentation based on linear
relationship between intensity and complex-decorrelation in optical coherence tomography angiography," Quantitative
Imaging in Medicine and Surgery 11, 895 (2021).
22. S. Kushner-Lenhoff, Y. Li, Q. Zhang, R. K. Wang, X. Jiang, and A. H. Kashani, "OCTA derived vessel skeleton density
versus flux and their associations with systemic determinants of health," Investigative Ophthalmology & Visual Science 63,
19-19 (2022).
23. M. Alam, D. Le, J. I. Lim, and X. Yao, "VASCULAR COMPLEXITY ANALYSIS IN OPTICAL COHERENCE
TOMOGRAPHY ANGIOGRAPHY OF DIABETIC RETINOPATHY," Retina (Philadelphia, Pa.) 41, 538-545 (2021).
24. M. Alam, D. Le, J. I. Lim, and X. Yao, "Vascular complexity analysis in OCT angiography of diabetic retinopathy," Retina
(Philadelphia, Pa.) 41, 538 (2021).
25. Á. Nyúl-Tóth, S. Tarantini, J. DelFavero, F. Yan, P. Balasubramanian, A. Yabluchanskiy, C. Ahire, T. Kiss, T. Csipo, and
A. Lipecz, "Demonstration of age-related blood-brain barrier disruption and cerebromicrovascular rarefaction in mice by
longitudinal intravital two-photon microscopy and optical coherence tomography," American Journal of Physiology-Heart
and Circulatory Physiology 320, H1370-H1392 (2021).
26. K. Flurkey, J. M. Currer, and D. Harrison, "Mouse models in aging research," in The mouse in biomedical research (Elsevier,
2007), pp. 637-672.
27. F. Yan, G. Gunay, T. I. Valerio, C. Wang, J. A. Wilson, M. S. Haddad, M. Watson, M. O. Connell, N. Davidson, and K.-M.
Fung, "Characterization and quantification of necrotic tissues and morphology in multicellular ovarian cancer tumor
spheroids using optical coherence tomography," Biomedical Optics Express 12, 3352-3371 (2021).
28. F. Yan, C. Wang, J. A. Wilson, M. O’Connell, S. Ton, N. Davidson, M. Sibichan, K. Chambers, A. Ahmed, and J. Summers,
"Visually guided chick ocular length and structural thickness variations assessed by swept-source optical coherence
tomography," Biomedical optics express 12, 6864-6881 (2021).
29. C. Wang, P. Calle, N. B. Tran Ton, Z. Zhang, F. Yan, A. M. Donaldson, N. A. Bradley, Z. Yu, K.-m. Fung, C. Pan, and Q.
Tang, "Deep-learning-aided forward optical coherence tomography endoscope for percutaneous nephrostomy guidance,"
Biomedical Optics Express 12, 2404-2418 (2021).
30. C. Wang, P. Calle, J. C. Reynolds, S. Ton, F. Yan, A. M. Donaldson, A. D. Ladymon, P. R. Roberts, A. J. de Armendi, K.-
m. Fung, S. S. Shettar, C. Pan, and Q. Tang, "Epidural anesthesia needle guidance by forward-view endoscopic optical
coherence tomography and deep learning," Scientific Reports 12, 9057 (2022).
31. C. Wang, J. C. Reynolds, P. Calle, A. D. Ladymon, F. Yan, Y. Y. Yan, S. Ton, K. M. Fung, S. G. Patel, Z. X. Yu, C. L. Pan,
and Q. G. Tang, "Computer-aided Veress needle guidance using endoscopic optical coherence tomography and convolutional
neural networks," J Biophotonics 15(2022).
32. C. Wang, P. Calle, J. Reynolds, N. B. T. Ton, F. Yan, A. Donaldson, A. Ladymon, P. Roberts, A. De Armendi, K.-M. Fung,
S. Shettar, C. Pan, and Q. Tang, Endoscopic optical coherence tomography for epidural anesthesia guidance (Conference
Presentation), SPIE BiOS (SPIE, 2022), Vol. PC11949.
33. F. Yan, J. H. Ha, Y. Yan, S. B. Ton, C. Wang, B. Mutembei, Z. A. Alhajeri, A. F. McNiel, A. J. Keddissi, Q. Zhang, M.
Jayaraman, D. N. Dhanasekaran, and Q. Tang, "Optical Coherence Tomography of Tumor Spheroids Identifies Candidates
for Drug Repurposing in Ovarian Cancer," IEEE Transactions on Biomedical Engineering 70, 1891-1901 (2023).
34. C. Wang, Y. Liu, P. Calle, F. Yan, A. de Armendi, S. Shettar, K.-M. Fung, C. Pan, and Q. Tang, Feasibility of using
polarization-sensitive optical coherence tomography (PS-OCT) in epidural anesthesia guidance, SPIE BiOS (SPIE, 2023),
Vol. PC12368.
35. F. Yan, T. Valerio, C. Wang, W. Chen, and Q. Tang, Monitoring the microenvironment and microvasculature of primary
pancreatic tumor under photothermal-induced immunotherapy by optical coherence tomography (Conference Presentation),
SPIE BiOS (SPIE, 2023), Vol. 12380.
36. T. Valerio, F. Yan, C. Wang, Q. Tang, and W. Chen, Longitudinally detecting collagen progression within multicellular
pancreatic tumor spheroids using polarization-sensitive optical coherence tomography (Conference Presentation), SPIE
BiOS (SPIE, 2023), Vol. 12380.
37. C. Wang, Y. Liu, P. Calle, F. Yan, N. Bradley, K.-M. Fung, S. Patel, Z. Yu, C. Pan, and Q. Tang, Percutaneous nephrostomy
guidance by a polarization-sensitive optical coherence tomography probe, SPIE BiOS (SPIE, 2023), Vol. PC12353.
38. M. M. Khansari, W. O’Neill, J. Lim, and M. Shahidi, "Method for quantitative assessment of retinal vessel tortuosity in
optical coherence tomography angiography applied to sickle cell retinopathy," Biomedical Optics Express 8, 3796-3806
(2017).
39. J.-H. Lee, S. Stefan, K. Walek, J. Nie, K. Min, T. D. Yang, and J. Lee, "Investigating the correlation between early vascular
alterations and cognitive impairment in Alzheimer’s disease in mice with SD-OCT," Biomedical Optics Express 14, 1494-
1508 (2023).
40. P. Shin, W. Choi, J. Joo, and W.-Y. Oh, "Quantitative hemodynamic analysis of cerebral blood flow and neurovascular
coupling using optical coherence tomography angiography," Journal of Cerebral Blood Flow & Metabolism 39, 1983-1994
(2019).