In our study, we evaluated the CFD of contralateral eyes of nAMD and PCV with OCTA, and found nAMD-contralateral eyes had significantly lower CFD compared with PCV and control eyes, while the difference wasn’t statistically significant between PCV group and control. Although CFD was found negatively correlates with aging(17), it is unlikely that aging itself can account for the difference, since PCV and AMD group were age-matched. Another important factor is the existence of drusen, which is considered a hallmark of dry AMD. In this study, nAMD group had higher rate of drusen existence (42.9%) in the fellow eyes, but the difference didn’t reach a significant threshold compared with PCV group (22.2%, P = 0.063). Besides, drusen existence was found negatively correlated with CFD in areas with a radius of 1.00 and 1.50 mm, but not 3.00 mm, indicating drusen existence primarily associated with decreased CFD of sub-foveal area, not the entire macula. Our finding is consistent with a previous study that vascular density was inversely associated with sub-RPE deposit density(18). Although there is a myriad of overlap between PCV and nAMD, the difference of CFD in their contralateral eyes may serve as a proof of their heterogeneity.
The interplay of RPE and CC loss has always been a hotspot in the pathogenesis of AMD, but their sequential order remains controversial. In various pathological studies, CC lost is proven to precede RPE degeneration and drusen formation(19, 20) and with OCTA, Nassisi et al found that CFD predicts the development and enlargement of drusen(21). In addition, lower choroidal perfusion detected with laser Doppler flowmetry was a risk factor for developing CNV in the fellow eyes of nAMD patients(12), and apparent neovascular buds were detected adjacent to areas of CC loss in histopathological study(20). These findings reinforce the role of CC loss in the pathogenesis of in both dry and neovascular AMD. On the other hand, VEGF secreted by RPE is vital for the maintenance of CC(22), and abnormal RPE morphology and function extends the area of CC loss in various geographic atrophy studies(23). In a histopathological including both forms of AMD, Mcleod et al (23) found a linear relationship between the loss of RPE and CC in GA, while CC dropout was evident in the absence of RPE, and they proposed the primary insult in GA and nAMD may arise from different levels, namely RPE and CC respectively. Overall, the cause-and-consequence relationship of these two surrogate markers remains a challenge, yet the pathology of AMD, despite wet or dry, lies in the RPE-Bruch’s membrane-CC complex.
While the CFD of PCV-contralateral eyes wasn’t different from control, indicating RPE-Bruch’s membrane-CC complex isn’t involved in the preclinical stage of PCV and may be a downstream effect secondary to primary pathology. Indeed, PCV is a well-recognized disease within pachychoroid disease spectrum, and engorgement of vortex vein is often observed, with correlating choroidal hyperpermeability(24), also confirmed by the pathology showing atherosclerotic change of choroid vessel wall, massive exudation of fibrin and blood plasma at polypoidal lesion(25, 26). Apoptosis of smooth muscle cells and choroidal endothelial cells were also observed(25). Chen et al induced polyp-like structures by ligating vortex veins in cynomolgus monkeys(27) These findings above suggest a role of choroidal hemodynamics in PCV pathogenesis(28).
A plethora of studies investigated the difference of choroidal morphology between PCV and nAMD. Subfoveal choroidal thickness (SFCT) is often used as an index, but it fluctuates with circadian rhythm and correlates with age and refractive errors(29). Bakthavatsalam et al(29) found that choroidal vascular index (CVI) of nAMD was lower than that in PCV (64.94 vs 62.54), but the difference wasn’t statistically significant (P = 0.10). Pachyvessels especially diffuse pattern were observed more commonly in thick-choroid PCV(30), and vascular area of typical PCV was significantly larger than nAMD(31). All aforementioned results indicate the two diseases are heterogeneous in terms of choroidal morphology.
Our study had the limitations that are inherent as a retrospective cross-sectional study. Besides, DM, hypertension and smoking status was collected from patients’ past medical records which were recorded in a self-report manner, thus not accurate enough to be included into multivariate analysis. Nevertheless, to the best of our knowledge, this is the first study that provided quantitative analysis of choriocapillaries among the fellow eyes of PCV, nAMD, and healthy eyes. Our study may provide evidence for the heterogeneity of nAMD and PCV.