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Assessment of the outer retina and choroid in white matter lesions participants using swept‐source optical coherence tomography

Abstract Purpose To assess the three‐dimensional outer retina thickness and choroid in eyes with white matter lesions (WMLs) using swept‐source optical coherence tomography (SS‐OCT). Methods Participants without dementia and stroke with cerebral WMLs were enrolled in our study. Optical coherence tomography (OCT) and OCT angiography (OCTA) were used to image and evaluate the outer retinal layer, choroidal structure, and perfusion of the choriocapillaris, microvessels of the choroid, respectively. Measurement of the outer retinal thickness, choroidal thickness and perfusion of the choriocapillaris was done by the SS‐OCT tool. Results Thirty‐one eyes from 16 WMLs and 40 eyes from 20 healthy controls were included in the data analyses. Outer retinal thickness was significantly reduced (P < .001) in WMLs participants when compared to healthy controls. Choroidal thickness was also significantly reduced (P < .001) in WMLs participants when compared to healthy controls. Choriocapillaris perfusion was significantly reduced (P = .002) in WMLs when compared to healthy controls. A significant correlation (Rho = .392, P = .032) was seen between the outer retinal thickness and choriocapillaris perfusion in WMLs participants. Conclusions Assessing retinal thickness and choroidal changes with the SS‐OCTA as a proxy for WML could prove to be a potentially valuable tool for early detection of cognitive decline and other neurodegenerative diseases.


INTRODUCTION
Recent years have seen a large increase in life expectancy due in part to a substantial decline in death rates in aging individuals. With increased long life comes an augmented peril of experiencing maladies, which increase in prevalence with increasing age such as Alzheimer's disease, the commonest cause of dementia (Prince et al., 2015). The projected rise in the number of the aging population has fueled clinical practitioners and researchers to plan for the care of the rising number with dementia and develop biomarkers to help in the early detection of these aging disorders; early detection will be pivotal in its prevention and facilitate therapeutic measures as well.
White matter lesions (WMLs), a common radiologic finding in the aging population, have been reported to be the predictable substrate for dementia and other cerebral small vessel diseases such as ischemic stroke (Peng et al., 2020). WMLs have been reported to be a product of ischemic impediments associated with the microcirculation of the brain and appear hyperintense on magnetic resonance imaging (MRI) scans (Wong, 2002). The presence of WMLs on radiologic scans increases the risk of cognitive decline and dementia (Miyao et al., 1992). Besides, recent reports (Levit et al., 2020;Sorond et al., 2020) have shown the importance of white matter integrity in the development of age-related cognitive decline, and that neurovascular unit dysregulation and executive dysfunction often appear together WMLs. Thus, timely and effective approaches become critical as therapies are more likely to be successful in the early phase of the disease rather than the late phase.
Ophthalmological impairment has been reported to occur before the apparent clinical manifestation of most cerebral neurodegenerative disease (Colligris et al., 2018); these ophthalmological abnormalities have been reported to be associated with the visual cortex of the brain indicating the association between the eye and the brain (Ong et al., 2015). Moreover, reports have shown that similar mechanisms of cortical degeneration also occur in the retina and optic nerve (Ong et al., 2015). Recent imaging reports have suggested that dysfunction of the cerebral microcirculation may contribute to the WMLs disease cascade (Ong et al., 2015); it has been suggested that decreased blood flow occurs in WML which leads to neurotoxicity (Wang et al., 2016).
In vivo reports using the optical coherence tomography (OCT) have shown significant thinning of the choroid in patients with dementia and WMLs (Iyigundogdu et al., 2017;Tak et al., 2017); as such, the choroid has been suggested to be a novel early and non-invasive microvascular indicator in the eye for neuro-axonal death in the brain. The choroid has been reported to be affected in many retinal diseases (Mcleod et al., 2009) and neurodegenerative diseases such as dementia (Gharbiya et al., 2014). Alterations in choroidal homeostasis have been reported to occur in the aging population (Jirarattanasopa et al., 2012), even though it has not been reported comprehensively. Animal models of AD have shown significant alterations in the choriocapillaris (Asanad et al., 2019;Podoleanu & Rosen, 2008); moreover, atrophy of the choriocapillaris has been reported to occur in normal aging (Podoleanu & Rosen, 2008;Spaide, 2009). Since WMLs are substrates for both dementia and stroke (the most common neurodegenerative disease in the aging population), in vivo assessment of the choroidal structure and choriocapillaris may provide useful information on the possible pathological changes that occur in WML and give clues to changes that occur before the obvious neurodegenerative diseases.
Our current study aimed to quantitatively analyze the choroidal structure, choriocapillaris, and outer retina using the swept-source optical coherence tomography (SS-OCT) in subjects with WMLs. We also aimed to provide a more comprehensive understanding of the retinal choroid as a potential indicator for neurodegeneration in the brain.

METHODS
This observational cross-sectional study was approved by the Ethics Board of West China Hospital and followed the Declaration of Helsinki.
All participants enrolled in this study provided informed written consent before participating in this study.
Twenty participants who were free from dementia and stroke were

RESULTS
Thirty-one eyes from 16 WMLs and 40 eyes from 20 healthy controls were included in our data analyses. Four WMLs participants were excluded because they could not cooperate with the SS-OCT imaging while one eye of a WML participant was excluded due to low signal quality (SQ < 6). Demographics and clinical information are displayed in Table 1. The graphical representation of the outer retinal thickness and choroidal structure is shown in Figure 2. WML participants showed colder colors in the outer retina thickness and choroidal structure when compared with healthy controls as seen in Figure 2.

Comparison of macula and choroid between the two groups
Outer retinal thickness was significantly reduced (P < .001, Table 2) in WMLs participants (166.80 ± 6.52 µm) when compared to healthy controls (181.07 ± 11.96 µm). Choroidal thickness was also significantly reduced (P < .001, A significant correlation (Rho = .392, P = .032) was seen between the outer retinal thickness and perfusion of the choriocapillaris in WMLs participants.

DISCUSSION
The retinal choroid is a highly vascularized structure of the posterior eye, and similar to any microvessels in the body, it is likely to undergo structural and functional changes with increasing age. This may involve a reduction of its microvascular perfusion leading to the reduction of Wang & Bennett, 2012) which creates an ischemic setting alarming the structure of the choroid resulting in its thinning as seen in our report.
Choroidal thinning in WMLs may be associated with hypoperfusion due to the irregularities in the choriocapillaris as seen in our results or the atrophic changes in the choroid as aforementioned (Iyigundogdu et al., 2017;Tak et al., 2017). On the other hand, choroidal thinning may be the result of the decreased metabolic activity associated with Our study assessed the thickness of the outer retina in WML participants. A few reports have analyzed the outer retinal thickness of the retina in some neurodegenerative diseases such as Parkinson's disease (Garcia-Martin et al., 2014;Roth et al., 2014;Spund et al., 2013) and Alzheimer's disease (Uchida et al., 2018); however, the results of these

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of China (81870937, 82071320), and the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYG D180 09).