**2.1. Retinal vessel caliber**

diagnosed with type 2 diabetes. With these trends continuing, 642 million patients with

Patients with diabetes are at substantially increased risk of developing complications. In light of the cost of interventions implemented throughout the natural history of these complications, diabetes constitutes a tremendous clinical and public health burden that exceeds the resources of healthcare systems even in the most affluent countries. The International Diabetes Federation has reported that most countries spent 5–20% of their total healthcare budget on diabetes in 2015, which amounted to 673 billion US dollars in health expenditure worldwide. This figure is expected to increase to about 802 billion US dollars by 2040 [1].

The complications of diabetes are commonly divided into macrovascular complications including myocardial infarction, heart failure, and stroke, and microvascular complications including diabetic nephropathy, neuropathy, and retinopathy. Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. The incidence of DR increases with the duration of diabetes. After 20 years, nearly all patients with type 1 diabetes and more than

Current treatment guidelines target proliferative disease and macular edema, two sight threatening complications. The most common approaches are intravitreal injections of vascular endothelial growth factor (VEGF)-inhibiting agents or corticosteroids, laser treatments, and surgical interventions. These treatments are often sight saving, but are invasive and cost-prohibitive. Therefore, we need to shift our focus to targeting upstream events at earlier

The major health economic burden caused by the increasing number of patients diagnosed with diabetes raises the need to identify patients at high risk of developing DR and sight threatening complications. Reliable biomarkers that help to predict the development and pro-

A biomarker is traditionally defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention" [3]. In order to be useful in the prevention of DR, a biomarker should (1) non-invasively detect early preclinical disease before the first clinical signs of the disease appear, (2) be causally linked or be an indicator of a causal mechanism that leads to the development of the disease, and (3) be consistently and strongly associated with the disease [3, 4]. Suitable biomarkers should identify patients at low risk to defer DR screening intervals facilitating cost-effective management and optimized resource allocation. Furthermore, biomarkers should help to predict the progression of DR to the vision-threatening stage, and may forecast the response to different treatment modalities, facilitating individualized care [5]. Important factors for valid biomarkers are reproducibility and validity in different populations. Furthermore, their measurements must be quick, cost-effective, and

To date, many serum variables have been proposed to be associated with DR incidence and progression. According to the Diabetes Control and Complications Trial (DCCT), a median glycated hemoglobin (HbA1c) of 7.2% reduced DR incidence by 76% in patients

60% of those with type 2 diabetes will develop signs of DR [2].

diabetes are expected by 2040 [1].

10 Early Events in Diabetic Retinopathy and Intervention Strategies

stages of non-proliferative DR (NPDR).

gression of the disease have to be defined.

applicable in daily clinical decision-making [5].

Diabetic retinopathy is diagnosed clinically by the presence of microaneurysms and small hemorrhages visualized during fundoscopy. Assessing the presence and number of microaneurysms as well as their rate of formation and disappearance has been suggested to be an appropriate marker of retinal vascular damage and therefore DR progression [11]. However, there are microvascular changes that have been shown to antecede fundoscopically visible lesions of DR including microaneurysms.

Within the last decades and with the implementation of specialized computer software systems, grading of retinal vessel diameters to document generalized vessel narrowing or widening has become increasingly sophisticated, objective, and reliable. Multiple population-based studies have used these systems to calculate retinal vascular caliber in terms of the central retinal artery and vein equivalent (CRAE, CRVE), which summarizes the average diameter of the internal lumen of the vessel, reflecting the visualized erythrocyte column [12]. In sum, the results of these studies provide evidence for an association between larger venular caliber and DR in patients with type 1 [11, 13] as well as type 2 diabetes [14, 15], therefore being consistent with clinical experience. However, reported findings on arteriolar caliber remain contradictory. The population-based Multi-Ethnic Study of Atherosclerosis (MESA) study showed that arteriolar calibers are dilated in patients with diabetes [13], whereas other researchers claim that arteries tend to constrict in diabetes [14, 16].

stages of NPDR, research has provided evidence that retinal blood flow increases above normal levels [28–30], which may arise from the increased demand caused by tissue hypoxia due to capillary basement membrane thickening and capillary occlusion [29, 32]. In proliferative disease, retinal blood flow is decreased again as measured with different techniques: Blair et al. used the dye dilution technique to measure the mean circulation time (MCT) calculated as the difference between the mean venous and arterial retinal passage times, which turned out to be statistically significantly longer in the eyes with proliferative DR (PDR) than in healthy eyes or eyes with NPDR [33]. Laser Doppler flowmetry (LDF), which measures blood flow at the optic nerve head (ONH), and color Doppler imaging, also showed a greater reduction in total retinal blood flow in patients with PDR than in patients with NPDR or healthy individuals [34, 35]. Recently, several groups have demonstrated the potential of Doppler OCT for assessing retinal blood flow in the diabetic eye. Doppler OCT can also detect volumetric blood flow and provide information about the structural anatomy. As shown with the techniques mentioned above, eyes with PDR had statistically significantly decreased retinal blood flow compared with normal eyes [36], especially those that had been treated with panretinal photocoagulation [28, 37, 38]. However, acute elevations in blood glucose can still trigger an increase in blood flow [26]. This finding suggests that the chronic hyperglycemic state in diabetes mellitus is associated with a reduction in retinal blood flow, but the retina still is able to respond to increased metabolic rates associated with acutely raised blood glucose by

Potential Imaging Biomarkers in the Development and Progression of Diabetic Retinopathy

http://dx.doi.org/10.5772/intechopen.71747

13

The structure of the retinal capillary network is unique. It has to feed one of the highest metabolically active tissues while limiting the extent of the vascular beds to a minimum in order to prevent optical interference to the photoreceptors [39]. The inner retina is perfused by four interconnected capillary plexi that include the peripapillary capillary plexus which is found in the retinal nerve fiber layer (RNFL) adjacent to the optic nerve head (ONH), the superficial capillary plexus in the ganglion cell layer (GCL), as well as an intermediate (ICP) and a deep capillary plexus (DCP), which are located at the two borders of the inner nuclear layer (INL) [40]. Currently most segmentation algorithms display the ICP and DCP as one capillary layer. The three vascular layers unite in the center of the macula to form a terminal capillary ring surrounding the foveal avascular zone (FAZ). The outer retina and the photoreceptors are dependent on blood supplied by diffusion from the choriocapillaris. The early changes in capillary architecture and perfusion in patients with diabetes have not yet been definitely established, as assessing the human retinal microvasculature *in vivo* is very difficult due to its

FA, introduced in 1961, has been the gold standard imaging technique for assessing the retinal capillary network [41]. The value of this imaging modality is undeniable, but so are its limitations. First, dye leakage and the superimposition of capillary beds from the different retinal layers into a single two-dimensional image hinder a proper differentiation between the superficial and deep capillary plexi [42]. Furthermore, FA is a time-consuming and invasive technique which does not render it optimal for DR screening or frequent longitudinal

increasing retinal blood flow.

**2.4. The capillary network**

small size and low optical contrast.

The discrepancy between results of different studies may be due to differences between the study cohorts in demographic (e.g., distribution in age) and metabolic traits including blood glucose levels, duration of diabetes, and cardiovascular risk factors (such as hypertension/ hyperlipidemia) as well as differences in sample size, follow-up period, and the methods applied. Before retinal vascular caliber assessment can be used as a biomarker in clinical practice, age-, sex-, body size-, and blood pressure-specific normative data are required.
