Retinal biomarkers of Cerebral Small Vessel Disease: A systematic review

PLoS One. 2022 Apr 14;17(4):e0266974. doi: 10.1371/journal.pone.0266974. eCollection 2022.


Introduction: Cerebral Small Vessel Disease (CSVD), a progressive degenerative disorder of small caliber cerebral vessels, represents a major contributor to stroke and vascular dementia incidence worldwide. We sought to conduct a systematic review of the role of retinal biomarkers in diagnosis and characterization of CSVD.

Methods: We conducted a systematic review of MEDLINE, PubMed, Scopus, the Cochrane Library Database, and Web of Science. We identified studies of sporadic CSVD (including CSVD not otherwise specified, Cerebral Amyloid Angiopathy, and Hypertensive Arteriopathy) and the most common familial CSVD disorders (including CADASIL, Fabry disease, and MELAS). Included studies used one or more of the following tools: visual fields assessment, fundus photography, Optical Coherence Tomography and OCT Angiography, Fluorescein Angiography, Electroretinography, and Visual Evoked Potentials.

Results: We identified 48 studies of retinal biomarkers in CSVD, including 9147 cases and 12276 controls. Abnormalities in retinal vessel diameter (11 reports, n = 11391 participants), increased retinal vessel tortuosity (11 reports, n = 617 participants), decreased vessel fractal dimension (5 reports, n = 1597 participants) and decreased retinal nerve fiber layer thickness (5 reports, n = 4509 participants) were the biomarkers most frequently associated with CSVD. We identified no reports conducting longitudinal retinal evaluations of CSVD, or systematically evaluating diagnostic performance.

Conclusion: Multiple retinal biomarkers were associated with CSVD or its validated neuroimaging biomarkers. However, existing evidence is limited by several shortcomings, chiefly small sample size and unstandardized approaches to both biomarkers' capture and CSVD characterization. Additional larger studies will be required to definitively determine whether retinal biomarkers could be successfully incorporated in future research efforts and clinical practice.

Publication types

  • Systematic Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Cerebral Small Vessel Diseases* / complications
  • Evoked Potentials, Visual*
  • Fluorescein Angiography / adverse effects
  • Humans
  • Retina / diagnostic imaging


  • Biomarkers