Skip to main content

Advertisement

SpringerLink
Log in

The vessel density of the superficial retinal capillary plexus as a new biomarker in cerebral small vessel disease: an optical coherence tomography angiography study

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Background

Optical coherence tomography angiography (OCTA) is a novel and noninvasive technique for the quantitative assessment of retinal microvascular perfusion. Since the retinal and cerebral small vessels share similar embryological origins, anatomical features, and physiological properties, altered retinal microvasculature might provide a new perspective on the mechanisms of cerebral small vessel disease (CSVD).

Objective

We aimed to evaluate retinal vessel density (VD) in patients with CSVD using OCTA and identify associations with cerebral magnetic resonance imaging (MRI) markers and cognitive function.

Methods

We prospectively recruited 47 CSVD patients and 30 healthy controls (HCs) to participate in the study. All participants underwent OCTA to evaluate retinal microvascular perfusion. The VDs of the macular region in the superficial retinal capillary plexus (SRCP), deep retinal capillary plexus (DRCP), and foveal avascular zone (FAZ) were determined, along with the VD of the optic nerve head (ONH) in the radial peripapillary capillary (RPC) network. Additionally, cerebral MRI and cognitive function tests were performed.

Results

In the macula area, the VD of the CSVD patients was significantly lower than HCs in the temporal quadrant of SRCP. In the ONH area, CSVD patients had lower VD than HCs in the peripapillary RPC network. According to multiple linear regression analysis, decreased VD of the macular SRCP was associated with white matter hyperintensity scores after adjustment for age, hypertension, diabetes, and hyperlipidemia. Furthermore, the VD of the macular SRCP was significantly correlated with CSVD patients’ cognitive function, especially global cognition, memory function, attention function, information processing, and executive function.

Conclusion

OCTA revealed a significant decrease in retinal microvascular perfusion in CSVD patients, and retinal hypoperfusion was related to MRI markers and cognitive function, suggesting that these parameters could have potential utility as early disease biomarkers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Pantoni L (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9(7):689–701

    Article  PubMed  Google Scholar 

  2. Vermeer SE, Longstreth WJ, Koudstaal PJ (2007) Silent brain infarcts: a systematic review. Lancet Neurol 6(7):611–619

    Article  PubMed  Google Scholar 

  3. Debette S, Markus HS (2010) The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341(7767):288–288

    Google Scholar 

  4. Chen X, Wang J, Shan Y, Cai W, Liu S, Hu M, Liao S, Huang X, Zhang B, Wang Y, Lu Z (2019) Cerebral small vessel disease: neuroimaging markers and clinical implication. J Neurol 266(10):2347–2362

    Article  PubMed  Google Scholar 

  5. Montero-Odasso M, Hachinski V (2014) Preludes to brain failure: executive dysfunction and gait disturbances. Neurol Sci 35(4):601–604

  6. Telgte AT et al (2018) Cerebral small vessel disease: from a focal to a global perspective. Nat Rev Neurol 14(7):387–398

    Article  PubMed  Google Scholar 

  7. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S, American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia (2011) Vascular contributions to cognitive impairment and dementia. Stroke 42(9):2672–2713

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pantoni L, Garcia JH (1997) Pathogenesis of leukoaraiosis: a review. Stroke 28(3):652–659

    Article  CAS  PubMed  Google Scholar 

  9. London A, Benhar I, Schwartz M (2013) The retina as a window to the brain-from eye research to CNS disorders. Nat Rev Neurol 9(1):44–53

    Article  CAS  PubMed  Google Scholar 

  10. Hanff TC, Sharrett AR, Mosley TH, Shibata D, Knopman DS, Klein R, Klein BEK, Gottesman RF (2014) Retinal microvascular abnormalities predict progression of brain microvascular disease. Stroke 45(4):1012–1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mitchell P, Wang JJ, Wong TY, Smith W, Klein R, Leeder SR (2005) Retinal microvascular signs and risk of stroke and stroke mortality. Neurology 65(7):1005–1009

    Article  CAS  PubMed  Google Scholar 

  12. Cheung N, Mosley T, Islam A, Kawasaki R, Sharrett AR, Klein R, Coker LH, Knopman DS, Shibata DK, Catellier D, Wong TY (2010) Retinal microvascular abnormalities and subclinical magnetic resonance imaging brain infarct: a prospective study. Brain 133(7):1987–1993

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ikram MK, de Jong FJ, van Dijk EJ, Prins ND, Hofman A, Breteler MMB, de Jong PTVM (2006) Retinal vessel diameters and cerebral small vessel disease: the Rotterdam Scan Study. Brain 129(1):182–188

    Article  PubMed  Google Scholar 

  14. Hilal S, Ong YT, Cheung CY, Tan CS, Venketasubramanian N, Niessen WJ, Vrooman H, Anuar AR, Chew M, Chen C, Wong TY, Ikram MK (2014) Microvascular network alterations in retina of subjects with cerebral small vessel disease. Neurosci Lett 577:95–100

    Article  CAS  PubMed  Google Scholar 

  15. Dumitrascu OM, Demaerschalk BM, Valencia Sanchez C, Almader-Douglas D, O'Carroll CB, Aguilar MI, Lyden PD, Kumar G (2018) Retinal microvascular abnormalities as surrogate markers of cerebrovascular ischemic disease: a meta-analysis. J Stroke Cerebrovasc Dis 27(7):1960–1968

    Article  PubMed  Google Scholar 

  16. Spaide RF, Fujimoto JG, Waheed NK, Sadda SR, Staurenghi G (2018) Optical coherence tomography angiography. Prog Retin Eye Res 64:1–55

    Article  PubMed  Google Scholar 

  17. Lahme L, Esser EL, Mihailovic N, Schubert F, Lauermann J, Johnen A, Eter N, Duning T, Alnawaiseh M (2018) Evaluation of ocular perfusion in Alzheimer’s disease using optical coherence tomography angiography. J Alzheimers Dis 66(4):1745–1752

    Article  PubMed  Google Scholar 

  18. Bulut M, Kurtuluş F, Gözkaya O, Erol MK, Cengiz A, Akıdan M, Yaman A (2018) Evaluation of optical coherence tomography angiographic findings in Alzheimer’s type dementia. Br J Ophthalmol 102(2):233–237

    Article  PubMed  Google Scholar 

  19. Yoon SP, Thompson AC, Polascik BW, Calixte C, Burke JR, Petrella JR, Grewal DS, Fekrat S (2019) Correlation of OCTA and volumetric MRI in mild cognitive impairment and Alzheimer’s disease. Ophthalmic Surg Lasers Imaging Retina 50(11):709–718

    Article  PubMed  Google Scholar 

  20. Lanzillo R, Cennamo G, Criscuolo C, Carotenuto A, Velotti N, Sparnelli F, Cianflone A, Moccia M, Brescia Morra V (2018) Optical coherence tomography angiography retinal vascular network assessment in multiple sclerosis. Mult Scler 24(13):1706–1714

    Article  PubMed  Google Scholar 

  21. Feucht N, Maier M, Lepennetier G, Pettenkofer M, Wetzlmair C, Daltrozzo T, Scherm P, Zimmer C, Hoshi MM, Hemmer B, Korn T, Knier B (2019) Optical coherence tomography angiography indicates associations of the retinal vascular network and disease activity in multiple sclerosis. Mult Scler 25(2):224–234

    Article  PubMed  Google Scholar 

  22. Wang X, Jia Y, Spain R, Potsaid B, Liu JJ, Baumann B, Hornegger J, Fujimoto JG, Wu Q, Huang D (2014) Optical coherence tomography angiography of optic nerve head and parafovea in multiple sclerosis. Br J Ophthalmol 98(10):1368–1373

    Article  PubMed  Google Scholar 

  23. Cennamo G, Carotenuto A, Montorio D, Petracca M, Moccia M, Melenzane A, Tranfa F, Lamberti A, Spiezia AL, Servillo G, de Angelis M, Petruzzo M, Criscuolo C, Lanzillo R, Brescia Morra V (2020) Peripapillary vessel density as early biomarker in multiple sclerosis. Front Neurol 11:542

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lee JY, Kim JP, Jang H, Kim J, Kang SH, Kim JS, Lee J, Jung YH, Na DL, Seo SW, Oh SY, Kim HJ (2020) Optical coherence tomography angiography as a potential screening tool for cerebral small vessel diseases. Alzheimers Res Ther 12(1):73

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jia Y, Bailey ST, Hwang TS, McClintic SM, Gao SS, Pennesi ME, Flaxel CJ, Lauer AK, Wilson DJ, Hornegger J, Fujimoto JG, Huang D (2015) Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye. Proc Natl Acad Sci U S A 112(18):E2395–E2402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Di Maio LG et al (2020) Optical coherence tomography angiography findings in Huntington’s disease. Neurol Sci

  27. Al-Sheikh M et al (2017) Impact of image quality on OCT angiography based quantitative measurements. Int J Retina Vitreous 3:13

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hiroki M, Miyashita K, Yoshida H, Hirai S, Fukuyama H (2003) Central retinal artery Doppler flow parameters reflect the severity of cerebral small-vessel disease. Stroke 34(7):e92–e94

    Article  PubMed  Google Scholar 

  29. Doubal FN, MacGillivray TJ, Patton N, Dhillon B, Dennis MS, Wardlaw JM (2010) Fractal analysis of retinal vessels suggests that a distinct vasculopathy causes lacunar stroke. Neurology 74(14):1102–1107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mutlu U, Cremers LGM, de Groot M, Hofman A, Niessen WJ, van der Lugt A, Klaver CCW, Ikram MA, Vernooij MW, Ikram MK (2016) Retinal microvasculature and white matter microstructure. Neurology 87(10):1003–1010

    Article  PubMed  Google Scholar 

  31. McGrory S, Ballerini L, Doubal FN, Staals J, Allerhand M, Valdes-Hernandez MC, Wang X, MacGillivray T, Doney ASF, Dhillon B, Starr JM, Bastin ME, Trucco E, Deary IJ, Wardlaw JM (2019) Retinal microvasculature and cerebral small vessel disease in the Lothian Birth Cohort 1936 and Mild Stroke Study. Sci Rep 9(1):6320

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yu DY et al (1994) Intraretinal oxygen distribution in rats as a function of systemic blood pressure. Am J Phys 267(6 Pt 2):H2498–H2507

    CAS  Google Scholar 

  33. Chen M, Luo C, Zhao J, Devarajan G, Xu H (2019) Immune regulation in the aging retina. Prog Retin Eye Res 69:159–172

    Article  CAS  PubMed  Google Scholar 

  34. Khan U et al (2007) Risk factor profile of cerebral small vessel disease and its subtypes. J Neurol Neurosurg Psychiatry 78(7):702–706

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yamamoto Y, Akiguchi I, Oiwa K, Hayashi M, Kasai T, Ozasa K (2002) Twenty-four-hour blood pressure and MRI as predictive factors for different outcomes in patients with lacunar infarct. Stroke 33(1):297–305

    Article  CAS  PubMed  Google Scholar 

  36. Wardlaw JM, Sandercock PAG, Dennis MS, Starr J (2003) Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke 34(3):806–812

    Article  CAS  PubMed  Google Scholar 

  37. Wong SM, Jansen JFA, Zhang CE, Hoff EI, Staals J, van Oostenbrugge RJ, Backes WH (2019) Blood-brain barrier impairment and hypoperfusion are linked in cerebral small vessel disease. Neurology 92(15):e1669–e1677

    Article  CAS  PubMed  Google Scholar 

  38. Kaur C, Foulds WS, Ling EA (2008) Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res 27(6):622–647

    Article  CAS  PubMed  Google Scholar 

  39. Patton N, Aslam T, MacGillivray T, Pattie A, Deary IJ, Dhillon B (2005) Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J Anat 206(4):319–348

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lenin R, Thomas SM, Gangaraju R (2018) Endothelial activation and oxidative stress in neurovascular defects of the retina. Curr Pharm Des 24(40):4742–4754

    Article  CAS  PubMed  Google Scholar 

  41. Deal JA, Sharrett AR, Rawlings AM, Gottesman RF, Bandeen-Roche K, Albert M, Knopman D, Selvin E, Wasserman BA, Klein B, Klein R (2018) Retinal signs and 20-year cognitive decline in the Atherosclerosis Risk in Communities Study. Neurology 90(13):e1158–e1166

    Article  PubMed  PubMed Central  Google Scholar 

  42. Cheung CY, Ong SY, Ikram MK, Ong YT, Chen CP, Venketasubramanian N, Wong TY (2014) Retinal vascular fractal dimension is associated with cognitive dysfunction. J Stroke Cerebrovasc Dis 23(1):43–50

    Article  PubMed  Google Scholar 

  43. Zhang YS, Zhou N, Knoll BM, Samra S, Ward MR, Weintraub S, Fawzi AA (2019) Parafoveal vessel loss and correlation between peripapillary vessel density and cognitive performance in amnestic mild cognitive impairment and early Alzheimer’s disease on optical coherence tomography angiography. PLoS One 14(4):e0214685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jenkins AJ, Joglekar MV, Hardikar AA, Keech AC, O'Neal DN, Januszewski AS (2015) Biomarkers in diabetic retinopathy. Rev Diabet Stud 12(1–2):159–195

    Article  PubMed  PubMed Central  Google Scholar 

  45. Criscuolo C, Cennamo G, Montorio D, Carotenuto A, Strianese A, Salvatore E, Tranfa F, Cennamo G, Lanzillo R, Brescia Morra V (2020) Assessment of retinal vascular network in amnestic mild cognitive impairment by optical coherence tomography angiography. PLoS One 15(6):e0233975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Campbell JP, Zhang M, Hwang TS, Bailey ST, Wilson DJ, Jia Y, Huang D (2017) Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci Rep 7:42201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhu L, Zong Y, Yu J, Jiang C, He Y, Jia Y, Huang D, Sun X (2018) Reduced retinal vessel density in primary angle closure glaucoma. J Glaucoma 27(4):322–327

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the National Key R&D Program of China (nos. 2016YFC1300604, 2016YFC1305904, and 2018YFC1314200).

Author information

Author notes

  1. Xiaojing Wang, Qiang Wei and Xingqi Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Xiaojing Wang, Qiang Wei, Xingqi Wu, Shanshan Cao, Chen Chen, Yibing Yan, Zhi Geng, Yanghua Tian & Kai Wang

  2. Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, Hefei, 230032, China

    Xiaojing Wang, Qiang Wei, Xingqi Wu, Shanshan Cao, Chen Chen, Yibing Yan, Zhi Geng, Yanghua Tian & Kai Wang

  3. Collaborative Innovation Center of Neuropsychiatric Disorders and Mental Health, Hefei, 230032, China

    Qiang Wei, Yanghua Tian & Kai Wang

  4. Department of Neurology, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China

    Jun Zhang

Authors
  1. Xiaojing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiang Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xingqi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shanshan Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yibing Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhi Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yanghua Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kai Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethics approval

All procedures performed in the studies involving human participants were in accordance with the Scientific Research Projects Approval Determination of Ethics Committee of The First Affiliated Hospital of Anhui Medical University, with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All the experiments were conducted with the consent of the patient and his/her family, and written informed consent was obtained in accordance with the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Wei, Q., Wu, X. et al. The vessel density of the superficial retinal capillary plexus as a new biomarker in cerebral small vessel disease: an optical coherence tomography angiography study. Neurol Sci 42, 3615–3624 (2021). https://doi.org/10.1007/s10072-021-05038-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-021-05038-z

Keywords

Search

Navigation