Cerebral small vessel disease (CSVD) is commonly used to describe a disorder consisting of clinical, cognitive, neuroimaging, and neuropathological manifestations induced by the brain's small perforating arterioles, capillaries, and perhaps venules (1, 2). CSVD presents with lacunes, cerebral hemorrhage, white matter lesions (WMLs), microbleeds, and microstroke (3). The prevalence of CSVD in older adults (aged > 65 years) is estimated at 87%. Lacunar stroke, which is caused by small vessel disease, accounts for 25–50% of all ischemic strokes in China. Severe WMLs could lead to cognitive decline (vascular dementia), depression, abnormal gait, dyskinesia, dysphagia, and urinary incontinence (4). Hence, early screening for CSVD is of great importance.

The features of CSVD on magnetic resonance imaging (MRI) include de novo small subcortical infarcts, lacunes, white matter hyperintensities, enlarged perivascular spaces (PVS), microbleeds, and brain atrophy (5, 6). Currently, MRI is the most commonly used imaging modality in clinical practice to evaluate CSVD. However, the high cost and incompatibility of MRI with certain metallic components prevent its use as a screening method. Therefore, a simpler, more cost-effective screening modality is required. The retina and the optic nerve head are components of the central nervous system (7), and the anatomic, embryologic, and physiologic characteristics of the retinal blood vessels are similar to those of the cerebral small vessels (8–10). The retinal vasculature that is correlated with the development of the cerebral vasculature can be directly visualized with ophthalmoscopy or retinal photography findings and therefore could provide information regarding CSVD (9, 10).

Optical coherence tomography angiography (OCTA) is a novel technique used to optically dissect and visualize the retinal microvascular system through a layer-by-layer analysis. OCTA provides high-resolution images and does not require injection of contrast medium (8, 11, 12) and is thereby a promising potential method to detect CSVD. Previous studies involving OCTA and CSVD have either focused on patients with Alzheimer's disease (AD) or patients with mild cognitive impairment, or were limited to small cohorts (8). Moreover, previous studies have only explored the correlation between WMLs and fundus changes. However, different mechanisms of WMLs have not been discussed in terms of location. Therefore, this comprehensive study included an appropriate sample size to explore the correlation between different CSVD type and fundus changes indicated by OCTA parameters, suggesting the feasibility and effectiveness of OCTA in CSVD screening.

A total of 132 patients diagnosed with CSVD were screened at our center. Seventeen patients were excluded due to poor OCTA imaging quality. Finally, 115 patients (male: 40%, right eye: 50%) were enrolled and analyzed. The mean age was 65.11 ± 11.23 years. The leading comorbidity was hypertension (59.1%), whereas type 2 diabetes mellitus was the least prevalent (28.7%) (Table 1). The mean RPC network density was 47.34 ± 5.09%, inside disc capillary density was 48.47 ± 4.88%, parafoveal capillary density was 44.37 ± 6.92%, perifoveal capillary density was 45.29 ± 4.61%, and FAZ was 0.34 ± 0.28 mm².

Univariate analysis revealed significant correlation between the severity of DWMLs and hypertension (p = 0.014), older age (p < 0.001), and lower RPC network density (p = 0.017) (Table 2). Multivariate logistic regression analysis showed that RPC network density (OR: 0.909; 95% CI: 0.828–0.998; p = 0.046) was negatively correlated with the severity of DWMLs (Figure 1). The severity of PWMLs was correlated with hypertension (p < 0.001), hyperlipidemia (p = 0.031), older age (p < 0.001), and lower inside disc capillary density (p = 0.080) in univariate analysis. However, no independently correlated variable was found (Table 3).

Patients with lacunes were more likely to be associated with hypertension (p = 0.004), lower parafoveal capillary density (p < 0.001) and lower perifoveal capillary density (p = 0.015) of the SRCP, lower RPC network density (p = 0.004) and thinner RNFL (p = 0.04) compared to those without lacunes. Multivariate logistic analysis revealed that lower parafoveal capillary density of SRCP (OR: 0.889; 95% CI: 0.817–0.967; p = 0.006) and hypertension (OR: 3.156; 95% CI: 1.348–7.392; p = 0.008) were independently correlated with lacunes.

Patients in the moderate to severe PVS group had significantly higher blood pressure (p = 0.012), older age (p < 0.001), lower RPC network density (p = 0.001), thinner peripapillary RNFL (p = 0.004), and lower inside disc capillary density (p = 0.019). After multivariate logistic analysis, RPC network density showed a negative correlation with PVS severity (OR: 0.881; 95% CI: 0.779–0.995; p = 0.041).

There were significant differences between CMB patients and non-CMB patients regarding hypertension (p = 0.024), hyperlipidemia (p = 0.033), age (p = 0.037), and inside disc capillary density (p = 0.007) in the univariate analysis. However, no variables were significantly different after multivariate logistic regression analysis.

Recently, CSVD has garnered increasing attention, and there has been great demand for a simpler screening method for CSVD in clinical practice. Anatomical, embryologic, and physiological characteristics of retinal blood vessels are similar to those of cerebral small vessels (8–10). The retina is regarded as a direct extension of the diencephalon and shares similar angiogenesis patterns. Meanwhile, vessels in the cerebral cortex (50–200 μm) and those of the retina (50–170 μm) have similar diameters and are approximately equal in size. Physiologically, the retina has a highly isolated and protected vascular system similar to that of the brain (18, 19). In 1986, Hinton et al. (20) described how neuro-degenerative changes affected the retina, lending credence to the correlation between the retina and the brain. Moreover, the fundus is the only part of the body that enables direct observation of nerves and blood vessels, thereby providing a direct path reflecting the nerves and blood vessels of the brain.

OCTA, a non-invasive imaging technique that provides high-resolution volumetric data, has been widely used in clinical practice. However, OCTA has not been applied to evaluate the correlation between fundus vessels and CSVD. In 2018, Lahme et al. analyzed 74 patients with AD and demonstrated that the Fazekas score was significantly correlated with retinal flow density rather than the area of the FAZ. However, RNFL thickness was not included in their study (21). Further, den Haan et al. (14) enrolled patients with AD and found that vessel density in the outer ring of the macula was inversely associated with the Fazekas score, whereas no correlation was identified between the RNFL thickness or FAZ and the Fazekas score. Together, these studies focused on patients with AD or mild cognitive impairment, and the sample size was small. To date, the application of OCTA in the evaluation of CSVD is lacking. We conducted this study to explore the correlation between CSVD and fundus changes revealed by OCTA.

Patients with lower RPC density had a higher Fazekas score in DWMLs rather than in PWMLs. There are some possible explanations: (1) as indicated by histological findings, PWMLs are non-ischemic. However, microcystic infarcts and patchy rarefaction of myelin which are ischemic, are associated with DWMLs (22–24); (2) anatomically, the paraventricular white matter area might be more hemodynamically determined, because this area is supplied by non-collateralizing ventriculofugal vessels arising from the subependymal arteries originating from the choroidal arteries, or from the terminal branches of the ramistriate and ventriculofugal vessels that run toward the penetrating centripetal vessels coming from the pial surface supply. Hence, the blood supply is not solely from small cerebral vessels in the periventricular white matter areas (24, 25). Conversely, deep white matter is supplied by medullary arteries arising from the cortical branches of middle cerebral arteries and has a single blood supply system, thus being more susceptible to ischemia (26).

Our study revealed a close inverse correlation between the RPC density and the Fazekas score in DWMLs. However, no correlation was detected between the Fazekas score and capillary density of the inside disc or macula. We propose a possible reason is that there are two distinct circulatory systems within the disc, the central retinal artery (CRA) and the ciliary arteries, whereas the radial peripapillary of the disc is only supplied principally by recurrent retinal arterioles arising from branches of the CRA. As a result, the radial peripapillary of the disc is more susceptible to ischemia.

In Lahme's study, the correlation between the vessel density of the RPC and the Fazekas score of WMLs was also demonstrated, which is in agreement with the findings in our study (21). However, they also reported that the vessel density of the parafoveal was related to the Fazekas score, which differed from our results. This is possibly because their study focused on patients with AD; the sample size could have also contributed to differences in the results obtained.

The present study also revealed that the lower density of RPCs was not only related to DWMLs, but the severity of PVS. Doubal et al. (27) reported that enlargement of the PVS was associated with WMLs. The PVS serves as an important conduit for the drainage of interstitial fluid to the ventricles, and it could be affected by abnormalities of the blood-brain barrier (28). Therefore, the parallel formation mechanism between WMLs and PVS may lead to similar changes in the fundus and comparable trends in RPC density, which could explain our results (29).

Lacunes are caused by small vessel disease, and pathological vascular changes in lacunes were mainly lipid hyaline degeneration or micro atherosclerotic plaque (30). As reported previously, our study also indicated patients with lacunes exhibited lower vessel density of the parafoveal SRCP (14, 21). However, the underlying mechanism requires further exploration. We suspected that the possible reason might be that the vascular density of the parafovea was lower than that of the perifovea in healthy individuals; therefore, the parafovea may be more vulnerable to ischemia.

No independent relationship was established between deep vascular density or the thickness of the fibrous layer and lacunes. Within the retina, there were two distinct circulatory systems, the superficial retina was supplied by the CRA, and the deep retina was supplied by ciliary arteries. Unlike the ciliary arteries, the CRA is a terminal vessel. Animal studies have demonstrated that ciliary arteries transport a greater volume of blood than the retinal the blood flow (31, 32). Therefore, the deep retina with its greater blood supply was less affected by ischemia than the superficial, which may account for the lack of significant correlation between the deep vascular densities and lacunes. Further, no significant correlation was found between the thickness of the fibrous layer and lacunes, possibly because the fibrous layer is not affected in the early stage of the disease.

There were no significant differences in the parameters of the fundus between patients with and without CMB in this study. The mechanism of CMB is primarily amyloid deformation rather than ischemia, which could explain the results.

There are limitations in this study. First, this is a non-randomized study and a control group was not included. Second, although the sample size is relatively large, studies with even larger cohorts are required to confirm our conclusions. Nevertheless, our study provides practical and useful information regarding the application of OCTA in CSVD screening.

This study investigated the correlation between four types of cerebrovascular diseases and fundus changes revealed by OCTA in a relatively large cohort. To the best of our knowledge, this is the first study to simultaneously assess four types of CSVD and to analyze PWMLs and DWMLs in parallel. The correlation between fundus parameters and CSVD suggests that OCTA is a feasible screening method for CSVD. Further studies using OCTA for CSVD screening are required to confirm our findings. OCTA parameters correlated with CSVD, with the most important being the RPC network density, which was negatively correlated with the severity of DWMLs and PVS, indicating that OCTA is a promising potential method for CSVD screening.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved by the Ethics Committee of Shanghai Tenth People's Hospital (No. 21k253). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

WF, XZ, PG, and JW: conception and design. WF, XZ, MW, PL, PG, and JW: analysis and interpretation. WF, XZ, MW, PL, and JH: data collection. WF, XZ, and PG: writing the manuscript. WF, XZ, MW, PL, JH, PG, and JW: final approval of the article and overall responsibility. WF, XZ, PL, JH, PG, and JW: statistical analysis. JW: obtained funding. All authors contributed to the article and approved the submitted version.

This work was supported by Shanghai Municipal Key Clinical Specialty (shslczdzk06102), Shanghai Science and Technology Commission (19401972804), and Start-up Fund of Shanghai Tenth People's Hospital (04.03.16.002).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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