Highlight
– Longitudinal decreases in retinal vessel density (VD) measured by OCTA correlate with worsening cerebral small vessel disease (cSVD) markers such as increased white matter hyperintensity (WMH) volume and perivascular space (PVS) enlargement in stroke patients.
– Changes in deep retinal VD track with cognitive decline over 1 year, as measured by the Montreal Cognitive Assessment (MoCA).
– Baseline OCTA metrics predict future brain imaging and cognitive outcomes post mild ischemic stroke, suggesting a prognostic role.
– OCTA offers a promising, noninvasive retinal microvascular biomarker for monitoring cSVD progression and associated cognitive impairment.
Background
Cerebral small vessel disease is a leading cause of vascular cognitive impairment and contributes substantially to stroke morbidity worldwide. Characterized by pathological changes affecting small penetrating arteries, arterioles, venules, and capillaries, cSVD manifests radiologically as white matter hyperintensities, lacunes, cerebral microbleeds, and enlarged perivascular spaces on MRI. These contribute to progressive cognitive decline and increased risk for dementia.
The retina shares embryological and anatomical similarities with cerebral microvasculature, allowing retinal imaging as a potential window into cerebral microvascular health. Optical coherence tomography angiography (OCTA) enables high-resolution, noninvasive visualization and quantification of retinal microvascular networks, including vessel density, area of the foveal avascular zone, vessel diameter, tortuosity, and blood flow indices.
Cross-sectional studies have reported associations between retinal microvascular abnormalities on OCTA and markers of cSVD as well as cognitive impairment. However, longitudinal data to clarify whether OCTA metrics can reliably track cSVD progression and cognitive change over time or predict future outcomes are lacking. This knowledge is critical to validate OCTA as a monitoring and prognostic tool in cerebrovascular disease.
Study Design
This prospective longitudinal cohort study enrolled 189 patients from a hospital stroke service presenting with mild ischemic stroke, classified as lacunar or mild cortical stroke, with a modified Rankin Scale score ≤2, reflecting mild disabilities. Participants underwent detailed baseline assessments including OCTA imaging to measure retinal vessel density (VD) in superficial and deep layers, foveal avascular zone (FAZ) area, vessel radius, tortuosity, and flow index.
Concurrent brain MRI quantified cerebral small vessel disease markers: white matter hyperintensity (WMH) volume, basal ganglia perivascular space (PVS) volume, and mean diffusivity within normal-appearing white matter. Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA).
Follow-up evaluations with OCTA, MRI, and MoCA were conducted after 1 year to assess longitudinal changes. The analysis employed linear mixed-effects models accounting for confounders including age, sex, systolic blood pressure, smoking status, diabetes, stroke severity, disability, and stroke subtype.
Key Findings
Out of 189 participants at baseline (mean age 64.8 years; 37% female), 154 completed the 1-year follow-up.
- Retinal Vessel Density and cSVD Progression: Reductions in retinal vessel density over 1 year were robustly associated with increased WMH volume. Specifically, standardized beta coefficients indicated that decreased vessel density in the superficial vascular layer correlated with WMH progression (β = -0.045, 95% CI -0.067 to -0.023), similarly for the deep layer (β = -0.050, 95% CI -0.074 to -0.026).
- Associations with Perivascular Spaces: Interestingly, increased retinal vessel density coupled with reduced retinal flow was linked to enlargement of basal ganglia perivascular spaces, highlighting complex vascular remodeling processes.
- Cognitive Trajectory: Decrements in deep retinal vessel density tracked with worsening cognition as measured by lower MoCA scores over the 1-year period (β = 0.136, 95% CI 0.036 to 0.236), suggesting oxygen delivery or neurovascular coupling alterations impacting cognition.
- Prognostic Value of Baseline OCTA: Lower baseline vessel densities in both superficial and deep retinal layers independently predicted poorer cognitive performance at 1 year post-stroke (superficial: β = 0.125, 95% CI 0.043 to 0.207; deep: β = 0.242, 95% CI 0.162 to 0.322), indicating potential utility in risk stratification and monitoring.
Expert Commentary
This study provides compelling longitudinal evidence linking retinal microvascular changes to progression of cerebral small vessel disease and cognitive decline after mild ischemic stroke. The use of OCTA extends prior cross-sectional observations by demonstrating temporal relationships, supporting the hypothesis that retinal microvascular health mirrors cerebral small vessel pathology.
The findings highlight OCTA as a noninvasive, accessible imaging modality that could complement brain MRI and neuropsychological tests in clinical trials and potentially routine clinical practice to monitor cSVD trajectory. Such biomarkers are urgently needed given the absence of disease-modifying therapies and the heterogeneity in clinical course.
Limitations include the single-center design, relatively modest sample size, and focus on mild strokes, which may affect generalizability to severe cases or broader populations. Residual confounding despite adjustment is possible. Future multicenter studies with larger cohorts and extended follow-up are warranted to validate these results and evaluate OCTA’s prognostic accuracy compared to established imaging markers.
Mechanistically, alterations in retinal vessel density likely reflect systemic microvascular endothelial dysfunction, blood-brain barrier breakdown, inflammation, and ischemic injury pathways shared across cerebral and retinal vessels.
Conclusion
This prospective longitudinal study demonstrates that OCTA-derived retinal microvascular metrics associate with cerebral small vessel disease progression and cognitive decline over one year in patients after mild ischemic stroke. Baseline OCTA measurements also predict future cognitive and brain imaging outcomes. These findings endorse OCTA as a promising noninvasive biomarker to monitor microvascular pathology in stroke populations enriched for cSVD.
Integration of OCTA into clinical pathways could enhance early detection, individualized risk assessment, and evaluation of therapeutic interventions targeting microvascular health. Further large-scale, multi-ethnic longitudinal studies are needed to consolidate OCTA’s role in cerebrovascular and cognitive disorders.
Funding and Trial Registration
The study supported by institutional stroke research grants; specific funding details not provided in the source publication. No clinical trial registration number is stated.
References
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