Table_1_The association between retina thinning and hippocampal atrophy in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review.DOCX

IntroductionThe retina is the “window” of the central nervous system. Previous studies discovered that retinal thickness degenerates through the pathological process of the Alzheimer’s disease (AD) continuum. Hippocampal atrophy is one of the typical clinical features and diagnostic criteria of AD. Former studies have described retinal thinning in normal aging subjects and AD patients, yet the association between retinal thickness and hippocampal atrophy in AD is unclear. The optical coherence tomography (OCT) technique has access the non-invasive to retinal images and magnetic resonance imaging can outline the volume of the hippocampus. Thus, we aim to quantify the correlation between these two parameters to identify whether the retina can be a new biomarker for early AD detection.
MethodsWe systematically searched the PubMed, Embase, and Web of Science databases from inception to May 2023 for studies investigating the correlation between retinal thickness and hippocampal volume. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the study quality. Pooled correlation coefficient r values were combined after Fisher’s Z transformation. Moderator effects were detected through subgroup analysis and the meta-regression method.
ResultsOf the 1,596 citations initially identified, we excluded 1,062 studies after screening the titles and abstract (animal models, n = 99; irrelevant literature, n = 963). Twelve studies met the inclusion criteria, among which three studies were excluded due to unextractable data. Nine studies were eligible for this meta-analysis. A positive moderate correlation between the retinal thickness was discovered in all participants of with AD, mild cognitive impairment (MCI), and normal controls (NC) (r = 0.3469, 95% CI: 0.2490–0.4377, I2 = 5.0%), which was significantly higher than that of the AD group (r = 0.1209, 95% CI:0.0905–0.1510, I2 = 0.0%) (p < 0.05). Among different layers, the peripapillary retinal nerve fiber layer (pRNFL) indicated a moderate positive correlation with hippocampal volume (r = 0.1209, 95% CI:0.0905–0.1510, I2 = 0.0%). The retinal pigmented epithelium (RPE) was also positively correlated [r = 0.1421, 95% CI:(−0.0447–0.3192), I2 = 84.1%]. The retinal layers and participants were the main overall heterogeneity sources. Correlation in the bilateral hemisphere did not show a significant difference.
ConclusionThe correlation between RNFL thickness and hippocampal volume is more predominant in both NC and AD groups than other layers. Whole retinal thickness is positively correlated to hippocampal volume not only in AD continuum, especially in MCI, but also in NC.
Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, CRD42022328088.

引言
视网膜是中枢神经系统的“窗口”。既往研究发现，在阿尔茨海默病（Alzheimer’s disease, AD）谱系的病理进程中，视网膜厚度会发生退行性改变。海马萎缩是AD典型的临床特征与诊断标准之一。既往研究已报道正常衰老人群与AD患者存在视网膜变薄现象，但AD患者视网膜厚度与海马萎缩之间的关联仍不明确。光学相干断层扫描（Optical Coherence Tomography, OCT）技术可无创获取视网膜图像，磁共振成像则能勾勒出海马体积轮廓。因此本研究旨在量化这两项参数间的相关性，以明确视网膜能否作为AD早期检测的新型生物标志物。

方法
我们系统检索了PubMed、Embase与Web of Science数据库自建库至2023年5月的相关文献，以筛选探讨视网膜厚度与海马体积相关性的研究。采用纽卡斯尔-渥太华质量评价量表（Newcastle-Ottawa Quality Assessment Scale, NOS）对纳入研究的质量进行评估。经Fisher Z转换后，合并相关系数r值。通过亚组分析与Meta回归方法检验调节效应。

结果
初步检索得到1596篇文献，经标题与摘要筛选后排除1062项研究（其中动物模型研究99项，无关文献963项）。最终有12项研究符合纳入标准，其中3项因数据无法提取被排除，剩余9项研究可纳入本次荟萃分析。在所有受试者（包括AD患者、轻度认知障碍（Mild Cognitive Impairment, MCI）人群与正常对照（Normal Controls, NC））中，视网膜厚度与海马体积呈中度正相关（r=0.3469，95%CI：0.2490~0.4377，I²=5.0%），该相关性显著高于AD亚组（r=0.1209，95%CI：0.0905~0.1510，I²=0.0%），差异具有统计学意义（p<0.05）。在不同视网膜分层中，视盘周围视网膜神经纤维层（peripapillary retinal nerve fiber layer, pRNFL）与海马体积呈中度正相关（r=0.1209，95%CI：0.0905~0.1510，I²=0.0%）。视网膜色素上皮（Retinal Pigmented Epithelium, RPE）同样呈正相关趋势[r=0.1421，95%CI：-0.0447~0.3192，I²=84.1%]。视网膜分层与受试者人群是整体异质性的主要来源。双侧大脑半球的相关性无显著差异。

结论
相较于其他视网膜层，视盘周围视网膜神经纤维层厚度与海马体积的相关性在正常对照与AD亚组中更为显著。全视网膜厚度与海马体积呈正相关，这一关联不仅存在于AD谱系人群（尤其轻度认知障碍人群）中，在正常对照人群中同样存在。

系统评价注册：https://www.crd.york.ac.uk/PROSPERO/，注册号：CRD42022328088。