In order to develop novel and innovative methods for detection and treatment of early stage diabetic retinopathy,
we are answering the following questions:
Do neuronal or vascular defects underlie early stage diabetic retinopathy?
Diabetic retinopathy is currently diagnosed in the clinic with retinal vessel changes, such as vascular leakage, edema and neovascularization. The current recommendation for diabetic patients is to have a yearly fundus exam to detect these vascular changes. However, there is a growing body of research showing that retinal neurons exhibit dysfunction prior to vascular changes. We are studying the chronology of neuronal, vascular, and neuro-vascular defects in rodent models of diabetes using various functional and imaging techniques. Figure 1 shows the order of appearance of visual and retinal function deficits in a rat model of Type I diabetes. We are currently determining which functional measures occur first and the underlying pathology that causes them in order to develop targeted treatments.
What screening tools are most sensitive for detection of early stage diabetic retinopathy?
Our lab evaluates different visual tests as potential screening tools for early visual dysfunction in diabetic patients. We are currently focused on testing novel flash stimuli with a non-invasive electrophysiological test called the electroretinogram or ERG. The ERG is a recording of the full field potential of the retina in response to a flash of light (Figure 2).
Using flash stimuli with different luminance levels and/or frequencies, the ERG provides information about the health of retinal pathways (rod, cone) and retinal cell types (photoreceptors, bipolar cells, amacrine cells). Using rodent models of diabetes, we have demonstrated that dim flash stimuli reveals rod photoreceptor pathway defects in early stage diabetic retinopathy (Figure 3).
In addition, contrast sensitivity and spatial frequency thresholds, as measured by optokinetic tracking, are decreased in early diabetic retinopathy (Figure 4). We are currently testing these methods in human subjects with diabetes to determine if they show similar defects as observed in the rodent models.
Additionally, we are exploring the use of fluorescent markers to detect oxidative stress or other in vivo signs of retinal pathology. For instance, hydrocyanines are a family of dyes that fluoresce with different emission wavelengths after binding to reactive oxygen species. As shown in Figure 5, these molecules can detect oxidative stress in vivo in an induced model of photoreceptor degeneration. We continue to validate these markers in other retinal disease models to determine their potential clinical applications.
What neuroprotective treatments slow the rate of DR?
We are interested in developing pharmacological and rehabilitative strategies to slow the progression of vision loss. Our lab uses a number of functional, anatomical and molecular outcome measures to determine whether a particular treatment is neuroprotective. Current interests include non-invasive and pluripotent approaches like physical exercise, targeted pharmaceuticals such as L-DOPA, and anti-oxidant treatments like TUDCA. Our goal is to translate these findings to humans with ultimate use in the clinic. A small clinical trial is currently underway to test our functional screening methods for DR and the efficacy of L-DOPA.