## 2 Retinal Vascular Diseases
### Vessel Density at the Macula
#### 2.1.3 Early Detection of DR  
Microvascular damage occurs prior to the observation of retinopathy in clinical examination or fundus photography [61]. The initial diagnosis of NPDR usually detects DR at a relatively advanced stage of microscopic vascular changes, which were not clinically or angiographically detectable as proven by histological studies of cadaver eyes in humans [62]. The early detection of DR is effective in avoiding severe loss of vision in diabetic patients [63]. Early microvascular changes in diabetic retina in patients with no DR has been studied using OCTA. OCTA, being a non-invasive imaging modality, may be considered a very helpful tool for clinical screening of eyes of patients of diabetes with DR [64]. Several studies ([PERSON] et al. [65], [PERSON] et al. [34], [PERSON] et al. [35], [PERSON] et al. [66], [PERSON] et al. [67]) have demonstrated enlargement of FAZ area in diabetic patients regardless of DR existence. [PERSON] et al. [65] reported enlargement of FAZ in healthy controls compared to the eyes of diabetic patients without DR.  
[PERSON] et al. [34] revealed enlargement of FAZ in the SCP in healthy controls compared to the eyes of diabetic patients without DR and enlargement of FAZ in the DCP in healthy controls compared to the eyes of diabetic patients without DR.  
[PERSON] et al. [35] revealed enlargement of FAZ in the SCP in healthy controls compared to the eyes of patients of diabetes without DR and enlargement of FAZ in the DCP in healthy controls compared to the eyes of diabetic patients without DR.  
[PERSON] et al. [66] revealed enlargement of FAZ in the SCP in healthy controls compared to the eyes of diabetic patients without DR. [PERSON] et al. [67] revealed enlargement of FAZ in the SCP in healthy controls compared to the eyes of patients of diabetes without DR and enlargement of FAZ in the DCP in healthy controls compared to the eyes of diabetic patients without DR. Other studies ([PERSON] et al. [46], [PERSON] et al. [31], [PERSON] et al. [68], [PERSON] et al. [64]) reported no statistical significance of the difference in FAZ area in the SCP between diabetic subjects without DR and normal healthy controls. Table 3 lists the average areas of the FAZ in both normal and early DR cases. Figure 3: DR progression. A progressive reduction of vessel density with the advancement of the stage of DR. Vessel Density at the Macula  
One of the early characteristics of microvascular alteration in the retina of patients of diabetes is a reduction of VD. This reduction may be due to the alteration of retinal neurovascular autoregulation, which regulates blood flow in response to metabolic demands [69]. Some studies ([PERSON] et al. [46], [PERSON] et al. [31], [PERSON] et al. [68]) reported a statistical significance of the reduction of VD in DCP but not in SCP in diabetic eyes without DR when compared to healthy control eyes. Several studies ([PERSON] et al. [66], [PERSON] et al. [64], [PERSON] et al. [70]) found a statistically significant reduction of VD in both DCP and SCP in diabetic subjects without DR as compared to normal healthy subjects. Furthermore, they reported no significant correlation between average VD and duration of diabetes or HBA1c level. [PERSON] et al. [71] found that perfused capillary density (PCD) is elevated in diabetic subjects with no DR as compared to healthy subjects, and they suggested that PCD can be used as a preclinical biomarker of diabetic microvascular disease. The different findings between these studies may be related to the specific segmentation method employed. [PERSON] et al. [71] selectively isolated capillaries from non-capillary blood vessels, and their results revealed increased perfused capillary density. They suggested that this was an autoregulatory response to increased metabolic demand. Other authors [31,46] have not done that, which may explain their results of decreased vessel density in DCP. [PERSON] et al.