Computational modeling of retinal hypoxia and photoreceptor degeneration in patients with age-related macular degeneration

Abstract

Although drusen have long been acknowledged as a primary hallmark of dry age-related macular degeneration (AMD) their role in the disease remains unclear. We hypothesize that drusen accumulation increases the barrier to metabolite transport ultimately resulting in photoreceptor cell death. To investigate this hypothesis, a computational model was developed to evaluate steady-state oxygen distribution in the retina. Optical coherence tomography images from fifteen AMD patients and six control subjects were segmented and translated into 3D in silico representations of retinal morphology. A finite element model was then used to determine the steady-state oxygen distribution throughout the retina for both generic and patient-specific retinal morphology. Oxygen levels were compared to the change in retinal thickness at a later time point to observe possible correlations. The generic finite element model of oxygen concentration in the retina agreed closely with both experimental measurements from literature and clinical observations, including the minimal pathological drusen size identified by AREDS (64 μm). Modeling oxygen distribution in the outer retina of AMD patients showed a substantially stronger correlation between hypoxia and future retinal thinning (Pearson correlation coefficient, r = 0.2162) than between drusen height and retinal thinning (r = 0.0303) indicating the potential value of this physiology-based approach. This study presents proof-of-concept for the potential utility of finite element modeling in evaluating retinal health and also suggests a potential link between transport and AMD pathogenesis. This strategy may prove useful as a prognostic tool for predicting the clinical risk of AMD progression.

The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration

“…Emerging data has shed light on extra-mitochondrial sources of ROS specifically in the outer retina and even in the outer segment of photoreceptors [52,53]. It was previously shown that oxygen is mainly absorbed at the level of the photoreceptors [54] and thus this site is most prone to oxidative stress, both in physiology and pathology [55]. To build on that, it seems that blue light exposure on outer segment discs as well as ectopic oxidative phosphorylation in the outer segment both pose a greater need for effective free radical scavengers in the outer segment-RPE interface [56][57][58].…”

Transcriptomic analysis of the mouse retina after acute and chronic normobaric and hypobaric hypoxia

“…Recent evidence suggests that mild, but chronic hypoxic conditions, that may develop due to reduced choroidal blood flow and volume 5 – 7 , choroidal ischemia 8 , and accumulation of drusen may also be important for the development and progression of the non-exudative form of AMD 8 . The involvement of hypoxia in disease is further supported by recent computational models showing a strong correlation between hypoxia and retinal thinning during AMD development 9 .…”

Potential Role of Myeloid-Derived Suppressor Cells (MDSCs) in Age-Related Macular Degeneration (AMD)

“…Drusen material accumulating between the RPE and the Bruch's membrane diminish the oxygen supply from the choroid to the retina (96). RPE cells suffering from hypoxia can result in the release of vascular endothelial growth factor (VEGF) already prior to the production of inflammatory markers (97).…”