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. 2021 Aug 11;16(8):e0255362. doi: 10.1371/journal.pone.0255362

Detection of retinal changes with optical coherence tomography angiography in mild cognitive impairment and Alzheimer’s disease patients: A meta-analysis

Jingwen Hui 1,2,3,4,#, Yun Zhao 1,2,3,4,#, Shasha Yu 1,2,3,4, Jinfeng Liu 5, Kin Chiu 5,6,*, Yan Wang 1,2,3,4,*
Editor: Rayaz A Malik7
PMCID: PMC8357127  PMID: 34379663

Abstract

Objective

To assess retinal microvascular network impairments in the eyes of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) patients with optical coherence tomography angiography (OCTA).

Design

Systematic review and meta-analysis.

Methods

A literature search was conducted in the PubMed and EMBASE databases to identify relevant studies detecting retinal microvascular attenuation among AD, MCI patients and cognitively healthy controls (HCs) by OCTA. Data were extracted by Review Manager V.5.4 and Stata V.14.0.

Results

Eight investigations were included in this meta-analysis, with 150 AD patients, 195 MCI patients and 226 HCs were eligible for meta-analysis. Evidence based on these studies demonstrated that there was a significantly decreased vessel density (VD) of the Optovue group in superficial capillary plexus (SCP): WMD = -2.26, 95% CI: -3.98 to -0.55, p = 0.01; in deep capillary plexus (DCP): WMD = -3.40, 95% CI: -5.99 to -0.81, p = 0.01, VD of the Zeiss group in SCP:WMD = -0.91, 95% CI: -1.79 to -0.02, p = 0.05 and an enlarged fovea avascular zone (FAZ):WMD = 0.06, 95% CI: 0.01 to 0.11, P = 0.02 in OCTA measurements of MCI patients. Additionally, in OCTA measurements of AD patients, there was a significantly decreased VD in the SCP: WMD = -1.88, 95% CI: -2.7 to -1.07, p<0.00001. In contrast, there was no significant decrease in DCP nor enlargement of FAZ in AD patients.

Conclusion

Retinal microvascular alternations could be optimally screened in MCI patients detected by OCTA, which could be a warning sign of relative changes in the MCI before progressing to AD. Retinal microvasculature changes worth further investigation in larger scale clinical trials.

Introduction

Alzheimer’s disease (AD) is progressive neurodegenerative disease, and the most common cause of dementia with cognitive impairment in the elderly. An estimated 40 million people worldwide have AD, and due to extending lifespans, this number is only expected to increase [1]. While in the preclinical stage mild cognitive impairment (MCI), the cognitive function of patient declines surpasses the expectation when taking the age into consideration. Because of no impaired performance of daily life activities, it is a transitional period of time in which the crucial pathophysiologic changes of AD exist. However, the critical symptoms cannot be detected clearly [2]. Once AD is diagnosed, patient will have an irreversible process, leading to dementia starts. On average patient can live for 4.6 years longer once diagnosed [3]. MCI possibly is a suggestion of preclinical stage of AD. Therefore, early diagnosis of the preclinical stage is important before the irreversible process begins is important. High-risk target population for progression to AD are those who obtained the amnestic type of MCI [4, 5].

Early diagnostic efficient testing of AD and MCI is still challenging and difficult [6]. Nowadays, we rely on clinical evaluation to diagnose MCI, such as neuropsychological testing [7]. Neuroimaing findings of the brain and spinal‐fluid examination can offer objective analysis to correlate with patient’s cognitive changes. However, these methods are extremely expensive and invasive [8]. Therefore, the discovery of new noninvasive and economical screening tool for diagnosis of MCI and AD is a major goal of in current research and numerous people have dedicated into this field [9].

Due to the shared dicencephalic origin of the retina and brain, retina is regarded as an extension of the central nervous system (CNS) [10, 11]. There is homology between retinal and cerebral vasculature. Optical coherence tomography (OCT) is a technique that allows imaging of the retina with a micrometer resolution [12]. The advanced functional extension of OCT termed OCT- angiography (OCTA) [13] can help a detailed angiographic view of the retinal vascular network [14, 15].

The loss in retinal vessel density and expansion of the FAZ area detected by OCTA could reflect changes in the MCI patients. OCTA scans and parameters have demonstrated the loss of the retinal vessel density is related with preclinical AD, possibly sharing a useful approach to neurodegenerative progress. Taking these limitations of the previous meta-analysis into the consideration, a review on OCTA system were performed and meta-analyzed to assess the changes among MCI, AD patients and healthy controls (HCs). Studies with detailed examine parameters of MCI, AD and HC were included.

Methods

The meta-analysis was carried out in accordance with the guidance illustrated by the Meta-Analysis of Observational Studies statement [16].

Data sources and search strategy

Comprehensive literature searching was conducted by two independent reviewers (HJW and ZY). Relevant studies were identified by searching PubMed and Excerpta Medica Database (EMBASE) according to the following criteria:(Alzheimer’s disease [Title/Abstract] OR mild cognitive impairment [Title/Abstract] OR "AD[Title/Abstract]"mild Alzhermer’s disease) AND ("optical coherence tomography angiography"[Title/Abstract] OR "OCT angiography"[Title/Abstract]) OR OCTA[Title/Abstract] OR "angio-OCT"[Title/Abstract]. Clinical studies published in peer-reviewed journals before March 31st 2021 were included. The gray literature and unpublished data were also measured. The literatures were analyzed with the bibliographic database.

Study selection and data extraction

The inclusion criteria:

  1. Studied of MCI and AD patients or included the preclinical stage of AD

  2. Measurements recorded as the mean and standard deviation (SD)

  3. Observational comparative studies

  4. Research work in English

The exclusion criteria:

  1. Studies that used for analysis without measure the methods in subjects with AD, MCI, HC.

  2. Conference abstracts, letters to editor, non-English records, animal studies and case reports.

  3. Insufficient data to estimate a weighted mean difference (WMD).

  4. Duplicate study populations or redundant publications.

Quality assessment

Quality evaluation was independently conducted by three reviewers (HJW, ZY and YSS). The other two reviewers searched and contacted relevant research when the information were inaccessible (JFL and KC). After the duplicate literatures were removed, the titles and abstracts of the remained literatures were screened according to the inclusion criteria and the exclusion criteria. The following data were extracted from each study: the first author, year of publication, design, country or region, sample size, type of AD, mean age, OCTA device used and details of OCTA scans. We chose the larger scan for a more satisfying resolution when results were available in various sizes of scans in the same study.

Statistical analysis

Review Manager V.5.4 (Cochrane Collaboration, Oxford, United Kingdom) and Stata V.14.0 were used for statistical analysis. In the analysis, continuous variables extracted is the mean values and SDs can be figured out using WMDs and the 95% confidence intervals (CIs). The Chi-square test and I2 statistic were applied to assessing the heterogeneity in statistic, and the use of the random-effect model was for predicting the levels of heterogeneity. Publication bias was evaluated by Egger’s linear regression test and P<0.05 regarded as statistically significant.

Results

Original research work published between January 1st 2015 and March 31st 2021 were covered, the literature search yielded 48 results (Fig 1), of which 37 were removed after a title and abstract screen by inclusion/exclusion criteria. Another three studies were excluded because of lack of sufficient data for analysis after full-text checking of the remaining 11 studies. Eight cross-sectional OCTA studies on the retinal changes among AD, OCTAMCI patients, and HC were included in this meta-analysis [2, 6, 17–20, 30, 31]. Studies published between January 1st 2015 and March 31st 2021 were covered. In total, 150 AD patients, 195 MCI patients and 226 HCs were included in this meta-analysis (Table 1).

Fig 1. The flowchart of the research selection.

Fig 1

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A total of eight potentially relevant articles were identified from our search strategies across all databases and systematic review reference lists.

Table 1. Included studies using OCTA to assess the retinal microvasculature in Alzheimer’s disease (AD), mild cognitive impairment (MCI) patients and healthy controls (HC).

Reference No. of subjects and diagnosis Age (years) Gender (female/male) Mean VD in SCP Mean VD in DCP Mean FAZ (mm2)
Chua 2020 [17] 37 MCI 77.9±6.4 16/21 14.94±1.02 20.81±1.65 -
24 AD 74.9±6.0 17/7 14.78±1.14 20.42±1.60 -
29 HC 76.7±5.3 13/16 15.66±0.96 21.54±1.55 -
Criscuolo 2020 [5] 27 MCI 73.0±6.0 15/12 44.92±5.04 45.13±6.67 0.28±0.12
29 HC 73.1±7.0 15/14 48.12±4.53 50.58±4.69 0.19±0.06
Shin 2021 [18] 40 MCI 72.8±8.6 15/25 14.0±3.9 25.5±1.9 -
37 HC 69.0±10.4 20/17 16.3±2.5 25.6±1.8 -
Wang 2021 [19] 47 MCI 72.73±7.75 29/18 44±3.07 49.57±2.89 0.36±0.12
62 AD 71.81±7.98 35/27 44.66±3.36 49.42±3.4 0.34±0.11
49 HC 69.5±5.94 32/17 46.82±2.08 50.89±2.86 0.33±0.12
Wu 2020 [2] 21 MCI 67.81±5.96 9/12 50.37±2.33 48.09±3.88 0.37±0.06
18 AD 69.94±6.39 9/10 49.56±2.81 43.10±2.75 0.44±0.08
21 HC 68.67±5.85 10/11 50.47±2.72 52.28±2.89 0.26±0.07
Yan 2021 [20] 37 AD - - 15.8±6.975 28.8±8.147 -
29 HC - - 15.94±6.264 28.8±8.298 -
Yoon 2019 [30] 7 MCI 70.70±9.10 3/4 17.77±1.18 - 0.17±0.05
9 AD 75.20±7.50 5/4 18.31±0.52 - 0.17±0.10
16 HC 73.30±8.30 8/8 17.98±0.99 - 0.17±0.07
Zhang 2019 [31] 16 MCI 73.03±8.24 13/3 40.67±5.23 - -
16 HC 73.60±7.69 13/3 44.50±4.11 - -
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SCP: superficial capillary plexus; DCP: deep capillary plexus; (-): no enough data recorded in the article.

Overall, from these 8 studies on the mean vessel density (VD) in superficial capillary plexus (SCP) layer, 7 studies suitable for analysis were found including 113 AD (approximately 68 female) patients, 195 MCI (100 female) patients, and 197 healthy controls (111 female). For the mean VD in the deep capillary plexus (DCP) layer, we identified 4 studies suitable for analysis, which included 104 AD (61 female) patients, 132 MCI (69 female) patients, and 128 healthy controls (70 female). For the fovea avascular zone (FAZ) area, 4 studies were figured out suitable for the evaluation, this included 89 AD (49 female) patients, 104 MCI (56 female) patients, and 115 healthy controls (65 female). Table 1 presents the characteristics of all articles, and Figs 2 and 3 showed the main results of the meta-analysis.

Fig 2. Meta-analysis of vessel density (VD) for mild cognitive impairment patients versus healthy controls.

Fig 2

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Mean and standard deviation (SD) are included, with 95% confidence intervals (CIs), heterogeneity scores and overall effect in an inverse variance (IV) random effects model. The green square size represents the weight attributed to each study based on relative sample size. (A) VD in superficial capillary plexus (SCP) detected by Optovue. (B) VD in SCP detected by Zeiss. (C) VD in deep capillary plexus (DCP) detected by Optovue. (D) Area size of foveal avascular zone (FAZ) in mm2.

Fig 3. Meta-analysis of vessel density (VD) for Alzheimer’s disease patients versus healthy controls.

Fig 3

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Mean and standard deviation (SD) are included, with 95% confidence intervals (CIs), heterogeneity scores and overall effect in an inverse variance (IV) random effects model. The green square size represents the weight attributed to each study based on relative sample size. (A) VD in superficial capillary plexus (SCP) detected by Optovue. (B) VD in deep capillary plexus (DCP) detected by Optovue. (C) Area size of foveal avascular zone (FAZ) in mm2.

Due to the differences in OCTA technology and site for the segmentation of retinal layers among various types of devices, VD results in the studies were not compared among studies that used different machines. Moreover, VD used in different machine is either area-based measurements (Optovue), length-based measurements (Zeiss). Our analysis focused on the outcomes using the same machine. There were 4 studies used the Optovue OCTA machine to analysis VD in the SCP (Table 2, Fig 2A) between MCI patients and HC healthy controls. Because of the obvious heterogeneity (I2 = 70%), the random effects model was adopted to pool the data. The meta-analysis indicated that the average VD in MCI patients was declined obviously when comparing with that in health ones (WMD = -2.26, 95% CI: -3.98 to -0.55, p = 0.01, Fig 2A). The analysis of mean vessel density (length based) in the SCP layer in 3 Zeiss studies (Table 2, Fig 2B) between MCI and HC found significant heterogeneity (I2 = 64%) over the studies, so the data were pooled through the random effects model. The meta-analysis of these data showed that the mean VD in MCI patients was decreased significantly when comparing with that in healthy group (WMD = -0.91, 95% CI: -1.79 to -0.02, p = 0.05, Fig 2B). The meta-analysis of mean VD in DCP data showed that there was a significant heterogeneity (I2 = 80%) over 3 studies, using Optovue, so the random effects model pooled the data. The meta-analysis on that indicated that the average VD in DCP of MCI patients was declined significantly when comparing with that in the HC (WMD = -3.40, 95% CI: -5.99 to -0.81, p = 0.01, Fig 2C). Measurement of area size in the FAZ can be compared among different machines. In this part of the meta-analysis, we pooled 4 studies together using the random effects model due to the high heterogeneity (I2 = 79%). The data of the meta-analysis presented that the mean vessel density in the FAZ area of MCI patients was increased significantly compared with HC (WMD = 0.06, 95% CI: 0.01 to 0.11, p = 0.02, Fig 2D). Therefore, when compare MCI patients with healthy control, there was significant VD decrease in both SCP and DCP, together with enlargement of FAZ area.

Table 2. Measurements that were included 8 studies are shown, each study was identified by using either the Optovue or the Zeiss OCTA machines.

Study OCTA machine Superficial VD Deep VD FAZ area
Criscuolo et al. Optovue ↓MCI ↓MCI ↑MCI
Wang et al. Optovue ↓MCI↓AD ↓MCI↓AD ~MCI~AD
Wu et al. Optovue ~AD~MCI ↓AD↓MCI ↑AD↑MCI
Yan et al. Optovue ↓AD ~AD -
Zhang et al. Optovue - ~MCI/AD ~MCI/AD
Chua et al. Zeiss ↓MCI↓AD ↓AD~MCI -
Yoon et al. Zeiss ↓MCI~AD ↓MCI~AD ~MCI~AD
Shin et al. Zeiss ↓MCI ↓MCI ↑MCI
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(↑): indicates evidence of a significant increase in the case group compared to the control group. (↓): indicates a significant decrease, (-): not enough data, and (~): indicates no evidence of a significant difference.

In the 3 studies that Optovue OCTA machine used to compare the analysis of the mean VD (area-based) in the SCP layer between AD and HC figured out significance of heterogeneity (I2 = 0%) over the studies, so we pooled the data via fixed effects model. The meta-analysis of these data showed that the mean VD in AD patients was reduced significantly compared with that in the HC (WMD = -1.88, 95% CI: -2.7 to -1.07, p<0.00001, Fig 3A). However, the further analysis of VD in the DCP, and FAZ area there was no statistical difference (P>0.05, Fig 3B & 3C) between AD patients and HC. To sum up, the outcomes presented that a significance of vessel density decrease in the SCP of people with AD comparing with the healthy controls. To sum up, the outcomes presented that a significance of vessel density decrease in the SCP of people with AD comparing with the healthy controls.

Discussion

This meta analysis focused on retinal microvascular changes in AD, MCI patients and HC. Comparing with HC, there was decreased VD in both SCP and DCP together with enlarged FAZ area in the MCI patients. In the studies included in this analysis, there was decreased VD in SCP in AD patient.

There are two major issues to be considered when we do meta-analysis on OCTA images. First is the scan size of the image. In the current study, 6×6 mm2 OCTA images were analyzed. Although this may be more affected by movement artifacts, it can capture a larger macular area, which means that more retinal vessels are captured for better evaluation. For the studies included in the current analysis, the quality of the OCTA data was reliable. Second is the various machines for performing measurements. Each device uses specific algorithms to reconstruct the images and gives different terminology to describe the outcome. The Optovue uses AngioVue software which operates using a split-spectrum amplitude decorrelation angiography algorithm (SSADA). The Zeiss uses AngioPlex software which uses an optical microangiography (OMAG) approach. Topcon employs OCTA ratio analysis (OCTARA). Our study compared those results from different reports using same machine, the conclusion that MCI patients have decreased VD in both SCP and DCP was supported by both Optovue and Zeiss. Our study showed retinal capillary loss in the superficial and deep layers and an increased FAZ area in the retina on OCTA, manifesting the decrease of retinal microvascular density and impairment in MCI patients when comparing to the cognitively healthy controls. The changes our study identified supported the hypothesis that vascular impairment leading to hypoperfusion may contribute to the onset and progression of AD [21].

AD is known as a disease that mainly influence the brain and recent studies have shown that the retina could affected to some degree [22]. The retina is regarded as the window into the brain, of which the microvasculature may yield insightful information into the pathophysiology of early AD [9, 23]. Due to the homology between retinal and cerebral vasculature, retinal vascular network changes in MCI could be measured using OCTA. OCTA is a rapid and efficient imaging and testing approach of alternations in the retina correlated to MCI, whose progression shows the evolution of AD [24]. The loss in retinal vessel density and expansion of the FAZ area detected by OCTA could reflect changes in the MCI population [25, 26]. OCTA scans and parameters have demonstrated the loss of the retinal vessel density is related with preclinical AD, possibly sharing a useful approach to neurodegenerative progress [27]. Timely diagnosis of MCI plays a leading role in the evaluation of disease progression and treatment efficacy [28]. This is the first meta-analysis which covers all accessible high-quality studies and considers OCTA to assess microvascular impairment in the eyes of MCI and AD patients when taking cognitively healthy controls into consideration.

Most of these previous studies were conducted in AD and few used in MCI patients. While VD was reported decline in AD patient, those in MCI were limited and conflicting. The FAZ area difference between people with MCI patients and HC was unclear [28]. Thus, we summarized the related studies and found that reduced VD and enlarged FAZ area may highlight the role of retinal microvasculature in the MCI process rather than in the late stage when AD is diagnosed. MCI patients had significant enlargement of the FAZ area and notably decreased VD of the macula in the superficial and deep retinal layers. We analyzed the VDs of the SCP and DCP, which were the percentage of the peripapillary region occupied by superficial and deep capillaries, respectively [29]. Furthermore, we found a significant difference in the FAZ area between MCI patients and HCs, which suggests that the FAZ could be another useful indicator in the early stage of preclinical AD. However, the indication about the changes in VD of the DCP and FAZ area measurements are still controversial. Decreased VD especially in DCP at the stage of MCI might be useful to elucidate the mechanism of retinal capillary pathology in MCI. For instance, Yoon et al. [30] and Zhang et al. [31] showed a critically lower VD in the whole retina but not in the DCP layer, and no differences in the FAZ area were observed between them. Our meta-analysis found VD not only decreased in SCP but also DCP in MCI patients with significant FAZ area enlarged. This indicated the low perfusion status in the MCI patients in the retina and require further clinical investigation.

The meta-analysis also proved there was a significant VD reduction in the SCP of AD patients compared with HC. And no significant change in VD in DCP layer and FAZ area. Three studies using Optovue offered measurements of VD for the SCP and DCP and FAZ area between the AD patients and HC. Wang et al. (2021) [19] and Yan et al. (2021) [20] did not find evidence of a difference in SCP, DCP and FAZ area between AD and HCs. Wu et al. (2020) [2] found a change in DCP and FAZ but no change in SCP between AD patients and HCs. Comparing to HC, the significant decrease of VD in the SCP was found in MCI and AD patients. This is consistent with the reports that inner retinal thickness of AD patients detected by OCT, reducing retinal microvasculature correlated with loss of inner retinal neurons. VD decrease in DCP and enlargement of FAZ area in the MCI stage might be transient and compensated in the progression of AD.

There are some limitations of this meta-analysis: 1) Even if the sensitivity analysis was carried out with great care, the heterogeneities of some comparisons still important, possibly relating to factors including the use of manual measurements and the inclusion of different ethnicities. 2) Because of the insufficiency of published findings, some possibly influence on measuring the OCTA, like axial length which were not studied. If future studies had increased samples sizes, it would be more helpful to support the OCTA screening application of early MCI. 3) The process of progressing from a relatively healthy condition to the mild cognitive impairment stage may be long. 4) What need to be mentioned is that the metrics in the work here contain inherent limits which could lead to the inconsistent outcomes viewed while in the literature. So the meta-analysis was insufficient for the exploration on the specific timing and process of microvascular impairments according to the cross-sectional studies covered, meaning that we need more well-designed longitudinal studies.

To sum up, there is a significantly decreased VD and enlarged FAZ area in OCTA measurements between people with MCI and HC. The data indicate that retinal microvascular alterations could be optimally screened in MCI patients using OCTA, which could warn of relative changes in the brain before progressing to AD. There was a significantly decreased VD in SCP in OCTA measurements between AD patients and HC However, there was no significant change in VD in the DCP and FAZ area between AD patients and HC, which revealed that retinal microvascular changes could persistent in superficial layers than in deep layers. OCTA detection of the VD in the SCP might be a useful biomarker for MCI and AD diagnosis. In the future, investigations with a larger sample size are needed to assess the effectiveness of this method and verify the association of retinal microvasculature changes in MCI, AD and HCs.

Supporting information

S1 Checklist

(DOC)

Click here for additional data file. (56.5KB, doc)
S1 File. Newcastle-ottawa quality assessment scale case control studies.

(DOCX)

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Data Availability

All files are available from PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Embase (https://www.embase.com/landing?status=grey) following the protocol outlined in the article. Please see "Data sources and search strategy" and "Study selection and data extraction" in the Methods section for the search criteria used.

Funding Statement

This study was supported by grant from the National Natural Science Foundation of China(Grant No:81873684).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Lane CA, Hardy J, Schott JM (2018) Alzheimer’s Disease. Eur J Neurol.25,59–70. doi: 10.1111/ene.13439 [DOI] [PubMed] [Google Scholar]
  • 2.Wu J, Zhang X, Azhati G, Li T, Xu G, Liu F (2020) Retinal microvascular attenuation in mental cognitive impairment and Alzheimer’s disease by optical coherence tomography angiography. Acta Ophthalmol. 98(6),e781–e787. doi: 10.1111/aos.14381 [DOI] [PubMed] [Google Scholar]
  • 3.Song A, Johnson N, Ayala A, Thompson AC (2021) Optical Coherence Tomography in Patients with Alzheimer’s Disease: What Can It Tell Us? Eye Brain. 13,1–20. doi: 10.2147/EB.S235238 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Mitchell AJ, Shiri-Feshki M (2009) Rate of progression of mild cognitive impairment to dementia—meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand. 119,252–265. doi: 10.1111/j.1600-0447.2008.01326.x [DOI] [PubMed] [Google Scholar]
  • 5.Criscuolo C, Cennamo G, Montorio D, Carotenuto A, Strianese A, Salvatore E, et al. (2020) Assessment of retinal vascular network in amnestic mild cognitive impairment by optical coherence tomography angiography. PLoS One. 15(6),e0233975. doi: 10.1371/journal.pone.0233975 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Bulut M, Kurtuluş F, Gözkaya O, Erol MK, Cengiz A, Akıdan M, et al. (2018) Evaluation of optical coherence tomography angiographic findings in Alzheimer’s type dementia. Br J Ophthalmol. 102(2),233–237. doi: 10.1136/bjophthalmol-2017-310476 [DOI] [PubMed] [Google Scholar]
  • 7.Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7,270–279. doi: 10.1016/j.jalz.2011.03.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Mardin CY, Hosari S (2019) Optical coherence tomography angiography in neuronal diseases: Preliminary findings. Ophthalmologe. 116(8),714–721. doi: 10.1007/s00347-019-0883-5 [DOI] [PubMed] [Google Scholar]
  • 9.Jiang H, Wei Y, Shi Y, Wright CB, Sun X, Gregori G, et al. (2018) Altered Macular Microvasculature in Mild Cognitive Impairment and Alzheimer Disease. J Neuroophthalmol. 38(3),292–298. doi: 10.1097/WNO.0000000000000580 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Van de Kreeke JA, Nguyen HT, Konijnenberg E, Tomassen J, den Braber A, Ten Kate M, et al. (2020) Optical coherence tomography angiography in preclinical Alzheimer’s disease. Br J Ophthalmol. 104(2), 157–161. doi: 10.1136/bjophthalmol-2019-314127 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Yu SS, Tang X, Ho YS, Chang RC, Chiu K (2016) Links between the Brain and Retina: The Effects of Cigarette Smoking-Induced Age-Related Changes in Alzheimer’s Disease and Macular Degeneration. Front Neurol. 7,119. doi: 10.3389/fneur.2016.00119 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Wang L, Murphy O, Caldito NG, Calabresi PA, Saidha S (2018) Emerging Applications of Optical Coherence Tomography Angiography (OCTA) in neurological research. Eye Vis (Lond). 5,11. doi: 10.1186/s40662-018-0104-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Zhang Y, Wang Y, Shi C, Shen M, Lu F (2021) Advances in retina imaging as potential biomarkers for early diagnosis of Alzheimer’s disease. Transl Neurodegener. 10(1),6. doi: 10.1186/s40035-021-00230-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Koustenis A Jr, Harris A, Gross J, Januleviciene I, Shah A, Siesky B (2017) Optical coherence tomography angiography: an overview of the technology and an assessment of applications for clinical research. Br J Ophthalmol. 101(1),16–20. doi: 10.1136/bjophthalmol-2016-309389 [DOI] [PubMed] [Google Scholar]
  • 15.Lei J, et al. (2017) Repeatability and Reproducibility of Superficial Macular Retinal Vessel Density Measurements Using Optical Coherence Tomography Angiography En Face Images. JAMA Ophthalmol. 135,1092. doi: 10.1001/jamaophthalmol.2017.3431 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Stroup DF, Berlin JA, Morton SC (2000) Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA,283,2008–2012. doi: 10.1001/jama.283.15.2008 [DOI] [PubMed] [Google Scholar]
  • 17.Chua J, Hu Q, Ke M, Tan B, Hong J, Yao X, et al. (2020) Retinal microvasculature dysfunction is associated with Alzheimer’s disease and mild cognitive impairment. Alzheimers Res Ther, 12(1):161. doi: 10.1186/s13195-020-00724-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Shin JY, Choi EY, Kim M, Lee HK, Byeon SH (2021) Changes in retinal microvasculature and retinal layer thickness in association with apolipoprotein E genotype in Alzheimer’s disease. Sci Rep, 11(1):1847. doi: 10.1038/s41598-020-80892-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Wang X, Zhao Q, Tao R, Lu H, Xiao Z, Zheng L, et al. (2021) Decreased Retinal Vascular Density in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI): An Optical Coherence Tomography Angiography (OCTA) Study. Front Aging Neurosci,12:572484. doi: 10.3389/fnagi.2020.572484 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Yan Y, Wu X, Wang X, Geng Z, Wang L, Xiao G, et al. (2021) The Retinal Vessel Density Can Reflect Cognitive Function in Patients with Alzheimer’s Disease: Evidence from Optical Coherence Tomography Angiography. J Alzheimers Dis, 79(3):1307–1316. doi: 10.3233/JAD-200971 [DOI] [PubMed] [Google Scholar]
  • 21.Lee JY, Kim JP, Jang H, Kim J, Kang SH, Kim JS, et al. (2020) Optical coherence tomography angiography as a potential screening tool for cerebral small vessel diseases. Alzheimers Res Ther. 12(1),73. doi: 10.1186/s13195-020-00638-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Hansson O, et al. (2006) Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: A follow-up study. Lancet Neurol. 5,228–234. doi: 10.1016/S1474-4422(06)70355-6 [DOI] [PubMed] [Google Scholar]
  • 23.Querques G, Borrelli E, Sacconi R, De Vitis L, Leocani L, Santangelo R, et al. (2019) Functional and morphological changes of the retinal vessels in Alzheimer’s disease and mild cognitive impairment. Sci Rep. 9(1),63. doi: 10.1038/s41598-018-37271-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Zabel P, Kaluzny JJ, Wilkosc-Debczynska M, Gebska-Toloczko M, Suwala K, Zabel K, et al. (2019) Comparison of Retinal Microvasculature in Patients With Alzheimer’s Disease and Primary Open-Angle Glaucoma by Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci. 60(10),3447–3455. doi: 10.1167/iovs.19-27028 [DOI] [PubMed] [Google Scholar]
  • 25.Moein H-R, Novais EA, Rebhun CB, Cole ED, Louzada RN, Witkin AJ, et al. (2018) Optical coherence tomography angiography to detect macular capillary ischemia in patients with inner retinal changes after resolved diabetic macular edema. Retina Phila Pa. 38,2277–2284. doi: 10.1097/IAE.0000000000001902 [DOI] [PubMed] [Google Scholar]
  • 26.Kisler K, Nelson AR, Montagne A, Zlokovic BV (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci. 18,419–434. doi: 10.1038/nrn.2017.48 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Rispoli M, Savastano MC, Lumbroso B (2015) Capillary Network Anomalies in Branch Retinal Vein Occlusion on Optical Coherence Tomography Angiography. Retina. 35,2332–2338. doi: 10.1097/IAE.0000000000000845 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Pellegrini M, Vagge A, Ferro Desideri LF, Bernabei F, Triolo G, Mastropasqua R, et al. (2020) Optical Coherence Tomography Angiography in Neurodegenerative Disorders. J Clin Med. 9(6),1706. doi: 10.3390/jcm9061706 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.O’Bryhim BE, Apte RS, Kung N, Coble D, Van Stavern GP (2018) Association of Preclinical Alzheimer Disease With Optical Coherence Tomographic Angiography Findings. JAMA Ophthalmol. 136(11),1242–1248. doi: 10.1001/jamaophthalmol.2018.3556 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Yoon SP, Thompson AC, Polascik BW, Calixte C, Burke JR, Petrella JR, et al. (2019) Correlation of OCTA and Volumetric MRI in Mild Cognitive Impairment and Alzheimer’s Disease. Ophthalmic Surg Lasers Imaging Retina. 50(11),709–718. doi: 10.3928/23258160-20191031-06 [DOI] [PubMed] [Google Scholar]
  • 31.Zhang YS, Zhou N, Knoll BM, Samra S, Ward MR, Weintraub S, et al. (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. doi: 10.1371/journal.pone.0214685 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Rayaz A Malik

11 May 2021

PONE-D-21-08825

Detection of retinal changes with optical coherence tomography angiography in mild cognitive impairment and Alzheimer’s disease patients: a meta-analysis

PLOS ONE

Dear Dr. Wang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Whilst of interest, the reviewers have raised major concerns on the methodology and criteria of the meta-analysis.

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Rayaz A Malik, MBChB, PhD

Academic Editor

PLOS ONE

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Additional Editor Comments:

Both reviewers find the meta-analysis of interest and relevance.

However, they highlight major areas which need to be addressed.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: No

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This meta-analysis article shows that the retinal vessel density (RVD) in patients with MCI was significantly lower in superficial (SCP) and deep capillary plexus (DCP) and higher in fovea avascular zone (FAZ) compared to healthy controls (HC). However, there was no significant difference in RVD in these regions between patients with Alzheimer’s disease (AD) and HCs.

This paper requires major revision and English editing.

The conclusion that the authors draw from their meta-analysis that RVD could screened in MCI to predict AD is invalid since RVD is not associated with AD. They should provide a possible explanation on why there is no difference in RVD between patients with AD and HC. That of what is written in the 3rd paragraph in the discussion is not an explanation.

The authors should include vascular dementia (VaD) and mixed dementia separately in their meta-analysis. They might find an association of RVD with VaD and mixed dementia.

Need to define all abbreviations in the abstract. Need to define vessel density and its abbreviation in the introduction.

The statement that only 5 cross-sectional studies were included in the meta-analysis in the first paragraph in the results is inconsistent with the other results (8 studies for RVD in SCP etc.) and abstract.

Deeming the cognitive assessments for MCI diagnosis as “time-consuming” in the introduction is inappropriate. Repeating a battery of cognitive assessments is essential for diagnosis of MCI.

Correct “vessel length density” in the last sentence in the third paragraph in the results.

Add references in the discussion. Which studies showed decreased VD in AD? Need to discuss which studies were conflicting on the association of RVD with MCI?

The RVD measurements in the studies from Chua, Shin, Yan and Yoon are very low compared to the other studies. Please provide a reason for the differences (i.e. manual measurement methods) and mention specifically about the studies.

Reviewer #2: Manuscript Title: Detection of retinal changes with optical coherence tomography angiography in mild cognitive impairment and Alzheimer’s disease patients: a meta-analysis

Summary: This systematic review assesses differences in OCT-A vascular density measurements within superficial and deep retinal capillary vessels amongst patients diagnosed with Alzheimer’s disease or mild cognitive impairment compared to health controls. The study topic is of importance as non-invasive methods for detecting early cognitive decline would be significantly beneficial for screening and directing preventative interventions. However, several methodological issues in the conduction of the systematic review mean the conclusions are not supported by evidence as presented in the manuscript.

Major Issues:

1. The authors should elaborate further on the following statement: “Take these limitations of the previous meta-analysis into the consideration”. It is unclear which prior meta-analysis they are referring to as this is not discussed/referenced in the introduction.

a. There are a number of reviews assessing the association between OCT and AD, most recently by Chan et al 2019.

2. Further detail is needed in the inclusion criteria, in particular, what are the definitions of MCI, pre-clinical AD and AD used to select studies for the systematic review.

a. There authors should consider extracting data that would help quantify the level of MCI/AD in the included studies (e.g. MMSE score).

3. The authors should provide a detailed search strategy with the N for results for the given search terms and databases searched.

4. The attached risk of bias assessment appears to be for randomised-controlled trials and not for diagnostic studies. Furthermore, the risk of bias assessment is not clearly described in the manuscript as there is only the mention of a ‘Quality evaluation’.

5. A significant issue in comparing OCT-A vessel density measurements is the fact that measurements vary significantly between OCT-A devices and extraction techniques. Many VD extraction techniques are proprietary, therefore, it can be challenging to compare study measurements. Was the OCT-A device and extraction technique considered factors during the conduction of the systematic review/meta-analysis?

a. In Table 1, there are large differences in the VD measurements between the studies with some reporting SCP VD of ~14-16% and other studies ~40-50%.

b. This could affect the sizes of mean differences between sub-groups and potentially studies should be grouped according to OCT-A device and not-pooled together as they are currently.

6. The 6*6mm macula scans were chosen over 3*3mm scans by default but I would question whether they have a better ‘resolution’. Although the captured macula area is bigger for the 6*6mm which would capture more of retinal vessels, this can come at the cost of more artefacts (a 6*6mm may be more affected by movement artifacts). The authors could instead extract data from both macula size scans and perform a subgroup analysis on the basis of the imaged macula area (6mm2 vs 3mm2).

7. Data on confounders of OCT-A vessel density should be recorded, where available, e.g. diabetes status, hypertensive status & retinal co-pathology.

8. The finding that MCI is associated with retinal microvascular changes but not AD (and that OCTA-should be used for MCI screening) is not sufficiently supported by the evidence-base as presented in the manuscript. The heterogeneity in all the analyses was high (I2>75%), hence, the certainly that can be placed on the summary estimates is limited.

9. Erratum? – Please clarify and amend the errors below.

a. The footnote for Fig 1 describes “A total of 4 potentially relevant articles were identified from our search strategies across all databases and systematic review reference lists” but the figure shows 9 studies in the meta-analysis.

b. Later in the results it details “After removing of duplicates and screening of titles and abstracts, 7 studies remained, and the full text were reassessed” but figure 1 shows 9 full-text articles were reviewed.

c. There after it mentions that “37 articles were excluded due to duplicated” but the figure suggests there were 48 articles after the removal of duplicates. The reasons for exclusion for the 37 studies is not given in Figure 1 or supplementary data.

10. The manuscript would benefit from scientific editing services as it requires refinement to improve its readability.

Minor Issues:

• Was the protocol for the now submitted literature review and meta-analysis published with the a-prior research questions and methodology?

• Some acronyms in the abstract are not defined within the abstract.

• Spacing is inconsistent and sentences are adjoined in places.

• Table 1 SCP and DCP VD units (% area) should be included.

**********

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Reviewer #1: Yes: Georgios Ponirakis

Reviewer #2: No

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PLoS One. 2021 Aug 11;16(8):e0255362. doi: 10.1371/journal.pone.0255362.r002

Author response to Decision Letter 0

4 Jul 2021

Major Issues:

1. The authors should elaborate further on the following statement: “Take these limitations of the previous meta-analysis into the consideration”. It is unclear which prior meta-analysis they are referring to as this is not discussed/referenced in the introduction.

a. There are a number of reviews assessing the association between OCT and AD, most recently by Chan et al 2019.

We have already revised and elaborated this part in the article.

2. Further detail is needed in the inclusion criteria, in particular, what are the definitions of MCI, pre-clinical AD and AD used to select studies for the systematic review.

a. There authors should consider extracting data that would help quantify the level of MCI/AD in the included studies (e.g. MMSE score).

We have added the definitions of MCI, pre-clinical AD and AD in the revised manuscript.

3. The authors should provide a detailed search strategy with the N for results for the given search terms and databases searched.

4. The attached risk of bias assessment appears to be for randomised-controlled trials and not for diagnostic studies. Furthermore, the risk of bias assessment is not clearly described in the manuscript as there is only the mention of a ‘Quality evaluation’.

We made a new NOS chart to assess the risk of bias between the studies which were included in our meta-analysis.

5. A significant issue in comparing OCT-A vessel density measurements is the fact that measurements vary significantly between OCT-A devices and extraction techniques. Many VD extraction techniques are proprietary, therefore, it can be challenging to compare study measurements. Was the OCT-A device and extraction technique considered factors during the conduction of the systematic review/meta-analysis?

a. In Table 1, there are large differences in the VD measurements between the studies with some reporting SCP VD of ~14-16% and other studies ~40-50%.

b. This could affect the sizes of mean differences between sub-groups and potentially studies should be grouped according to OCT-A device and not-pooled together as they are currently.

We had noted the measurements differences between studies. We only compared the results and pooled the data together between studies which used same machine.

6. The 6*6mm macula scans were chosen over 3*3mm scans by default but I would question whether they have a better ‘resolution’. Although the captured macula area is bigger for the 6*6mm which would capture more of retinal vessels, this can come at the cost of more artefacts (a 6*6mm may be more affected by movement artifacts). The authors could instead extract data from both macula size scans and perform a subgroup analysis on the basis of the imaged macula area (6mm2 vs 3mm2).

The 6*6mm scans captured more of retinal vessels in macula area than 3*3mm which means that the 3*3mm scans area was included by 6*6mm.

7.Data on confounders of OCT-A vessel density should be recorded, where available, e.g. diabetes status, hypertensive status & retinal co-pathology.

All the participants in our study were excluded by some complications like DM, hypertension and other retinopathy.

8. The finding that MCI is associated with retinal microvascular changes but not AD (and that OCTA-should be used for MCI screening) is not sufficiently supported by the evidence-base as presented in the manuscript. The heterogeneity in all the analyses was high (I2>75%), hence, the certainly that can be placed on the summary estimates is limited.

In our study, we found that there was a significant difference of DCP and FAZ but no significant different of SCP between AD and HC. We concluded that retinal microvascular changes may occurred in different time.

9. Erratum? – Please clarify and amend the errors below.

a. The footnote for Fig 1 describes “A total of 4 potentially relevant articles were identified from our search strategies across all databases and systematic review reference lists” but the figure shows 9 studies in the meta-analysis.

b. Later in the results it details “After removing of duplicates and screening of titles and abstracts, 7 studies remained, and the full text were reassessed” but figure 1 shows 9 full-text articles were reviewed.

c. There after it mentions that “37 articles were excluded due to duplicated” but the figure suggests there were 48 articles after the removal of duplicates. The reasons for exclusion for the 37 studies is not given in Figure 1 or supplementary data.

We have already revised respectively in the article.

10. The manuscript would benefit from scientific editing services as it requires refinement to improve its readability.

The article has already been improved the fluency by scientific editing services.

Minor Issues:

• Was the protocol for the now submitted literature review and meta-analysis published with the a-prior research questions and methodology?

• Some acronyms in the abstract are not defined within the abstract.

• Spacing is inconsistent and sentences are adjoined in places.

• Table 1 SCP and DCP VD units (% area) should be included.

These issues were already solved in the article.

Decision Letter 1

Rayaz A Malik

15 Jul 2021

Detection of retinal changes with optical coherence tomography angiography in mild cognitive impairment and Alzheimer’s disease patients: a meta-analysis

PONE-D-21-08825R1

Dear Dr. Wang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Rayaz A Malik, MBChB, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The major concerns have been addressed. This analysis provides important insights on the use of OCT in MCI/dementia.

Reviewers' comments:

Acceptance letter

Rayaz A Malik

27 Jul 2021

PONE-D-21-08825R1

Detection of retinal changes with optical coherence tomography angiography in mild cognitive impairment and Alzheimer’s disease patients: a meta-analysis

Dear Dr. Wang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Rayaz A Malik

Academic Editor

PLOS ONE

Associated Data

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    S1 Checklist

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    S1 File. Newcastle-ottawa quality assessment scale case control studies.

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