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Diabetic Retinopathy is a neurodegenerative disorder

see more at Michael D. Abramoff, MD, PhD

Stephanie K. Lynch, Michael D. Abramoff. "Diabetic Retinopathy is a neurodegenerative disorder". Vision Research, Special Issue on Diabetic Retinopathy, 2017 [in press]. pre-print pdf. The final version is on Science Direct at https://doi.org/10.1016/j.visres.2017.03.003

This paper explains our reasoning and the historical context why we consider Diabetic Retinopathy a primary neuropathy. The ancient landmark articles referred to are hard to get, but in the public domain, so we listed them in the table below in chronological order.

 
Blancardiarticle thumbnail Leber article thumbnail Dickinson iarticle thumbnail Dickinson iarticle thumbnail Edmunds Article thumbnail
Blancardi S. Anatome Diabetis & Amaurosi laborantis. Anatomia practica rationalis... LXXX I(81). Amsterdam: Blancardi; 1688. p. 289-90. Leber TK. Über die Erkrankungen des Auges bei Diabetes mellitus. Albrecht von Graefes Arch Ophthalmol. 1875;21(3):206-337. Dickinson WH. Chapter II, Pathology. Diseases of the kidney and urinary derangements [Part I Diabetes]. London: Longmans, Green, and Co.; 1875. p. 30-66.

MacKenzie S. A Case of Glycosuric Retinitis, with Comments. (Microscopical Examination of the Eyes by Mr. Nettleship). Roy London Ophthal Hosp Rep. 1879;9:134.

 Edmunds W, Lawford JB. Examination of optic nerve from a case of amblyopia in diabetes. Trans Ophthalmol Soc UK. 1883;3:3160-78.
thumbnail of first page of Lewandowski article Orlandini 1904 article thumbnail ​thumbnail of first page of Lo Russo article thumbnail of first page of Ballantyne  
Lewandowsky M. Zur Lehre von der Cerebrospinalflüssigkeit. Z Klin Med. 1900;40:28. Orlandini O. Alterazioni della retina nella glicosuri asperimentale. Rivista veneta di scienze mediche. 1904; 40 (Tomo XXXX): 97-107. Lo Russo D. La Retinite Diabetica. Ann di ottal e Clinica Oculista di Roma. 1927;55:222-54. Ballantyne A, Loewenstein A. The Pathology of Diabetic Retinopathy. Trans Ophthalmol Soc UK. 1943;63:95-115.  

Diabetic retinopathy is a neurodegenerative disorder

Stephanie K. Lynch1, Michael D. Abràmoff1,2,3,4,*

1Department of Ophthalmology and Visual Sciences, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.

2Iowa Institute for Biomedical Imaging, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.

3Department of Electrical and Computer Engineering, University of Iowa, Iowa City, IA 52242.

4Department of Veterans Affairs, 601 US-6, Iowa City, IA 52246 USA.

* Corresponding author: michael-abramoff@uiowa.edu (orcid.org/0000-0002-3490-0037)

Abstract

Since 1875, controversy has ensued over whether ocular diabetic complications are primarily vasculopathic or neuropathic in nature. Here, we discuss the historical context by which diabetic retinopathy (DR) came to be considered a primary vasculopathy, in contrast to more recent data suggesting the importance of diabetic retinal neurodegeneration (DRN) as the primary manifestation of ocular diabetic damage. Unsurprisingly, DRN parallels other diabetic complications related to neuropathy. In general, there are three possible relationships between microvascular DR and DRN: i) microvasculopathy causes neurodegeneration; ii) neurodegeneration causes microvasculopathy or iii) they are mutually independent. The authors' group has recently produced experimental data showing that DRN precedes even the earliest manifestations of DR microvasculopathy. In combination with earlier studies showing that focal implicit time delays predicted future development of DR microvasculopathy in the same location, relationships i) and iii) are unlikely. As such, ii) is the most likely relationship: DRN is a cause of DR. Granted, additional studies are needed to confirm this hypothesis and elucidate the mechanism of diabetes-induced neurodegeneration. We conclude this review by proposing experimental approaches to test the hypothesis that DRN causes DR. If confirmed, this new paradigm may lead to earlier detection of ocular diabetic damage and earlier treatment of early DR, thereby preventing visual loss in people with diabetes.

Introduction

Since 1875, controversy has ensued over whether ocular diabetic complications are primarily vasculopathic or neuropathic in nature. Traditionally, diabetic retinopathy (DR) has been assumed to be and has been taught as a primary vasculopathy.1 More recently, however, as retinal diabetic neurodegeneration (DRN) has been studied extensively, it is now widely recognized that diabetes causes both a vasculopathy and a neuropathy. This leaves open the question whether vasculopathy precedes neuropathy or vice versa. Although there exists only circumstantial, but no conclusive, evidence, that neuropathy precedes vasculopathy, I invite you to consider the hypothesis that DR is a primary neurodegenerative disorder; in other words, DR begins as a neuropathy, which subsequently causes the classically described phenotype of diabetic microvascular retinopathy.2, 3

History of retinal vasculopathy and neurodegeneration

Diabetes was recognized as a systemic disease in antiquity, with many symptoms described in detail, especially by Aretaeus of Cappadocia. However, at that time, diabetes was a rare disease, and patients typically did not survive to the point at which ocular complications developed. In 1688, Blancardi, an anatomist in Amsterdam, published a study of practical anatomy that contained the first reference to a patient with diabetes suffering from visual loss. He described (translated from Latin): "A young girl suffered from diabetes for almost a year. Before her death, she suffered from blindness in both eyes, and she could see the light of neither sun nor candle. Her skull was opened, and we discovered a fluid filled region, […] which prevented the light from entering the optic nerve." 4

Many centuries passed before there was further documentation of visual loss from diabetes. In 1875, Leber, then practicing in Göttingen, Germany, published a crucial study on ocular complications from diabetes: Über die Erkrankungen des Auges bei Diabetes mellitus,5 and wrote (translated from German): "What is more likely than the hypothesis that similar processes, foci of capillary hemorrhages and fatty degeneration and vessel changes, that we suspect in the retina, analogous to the exhaustively studied histological findings in [nephritis], sometimes also occur in the optic nerve, the chiasma, and the optical tract, even further in the brain and possibly even in the optical centers of the brain." Leber thus ascribed the changes in DR to a primary vasculopathy. That same year, Dickinson, then practicing in London, wrote in his treatise on nephropathies the following: 6 "[...] the inference that diabetes is produced by substantial and constant changes in the nervous centres, none the less significant because, as with many other diseases of these structures, they are such as ordinarily to elude the naked eye. They are such indeed as to link symptoms with lesions as closely with natural as artificial glycosuria, and to give diabetes a definite place among the diseases of the nervous system." Therefore, as early as 1875, debate existed between experts on diabetes (i.e., Leber and Dickinson) as to whether diabetic complications reflected a primary vasculopathy or a primary neuropathy.

Diabetes as a primary retinal vasculopathy

In 1879, MacKenzie, then practicing at Moorfields in London, was the first to describe retinal microaneurysms in DR. Familiar with both Leber's and Dickinson's work, he wrote the following: "I cannot help differing from his conclusions, however, for Dr. Dickinson regards the peri-vascular extravasations and erosions of nervous structures as the cause of the symptoms in diabetes. To my mind the whole evidence points to the changes in the nervous system as well as those in the retina and other organs, being due to an altered condition of the blood. [...] the alterations in the nervous centers and in the eyes would appear to be coincident, rather than the latter sequential to the former."7 MacKenzie concluded that DR is a primary vasculopathy (although without substantial scientific evidence). Going forward, this conclusion was cited by landmark authors of studies on DR, such as Ballantyne and Loewenstein in 1943,8 Friedenwald in 1950,2 and Cogan in 1961.9 All of these authors endorsed the primary vasculopathy hypothesis for DR, largely based on MacKenzie's treatise. And thus today, most textbooks categorize DR under Vascular Diseases of the retina.1, 10, 11

Even though this seemed to establish DR as a primary vasculopathy, descriptions of early neuropathy remained a recurring theme in the literature henceforth. For example, Edmunds et al, wrote in 1883 "

"[…] that the optic nerves were not the only part of the nervous system affected. The changes found in the [optic] nerve appear to us to be too great to be secondary."12 In 1904, Orlandini wrote (translated from Italian): "Histological examination of the retina in de-pancreatised animals showed […] two types of alterations: alteration of nervous tissue (especially (above all) ganglion cells and nerve fibers), and of blood vessels."13 Finally, in 1927, Lo Russo described pathologic changes in cadaveric human diabetic retinas, including nerve fiber layer (NFL) and ganglion cell layer (GCL) thinning, as well as cavitation of the inner retina.14

Renewed interest in retinal neurodegeneration (DRN)

In 1961, Wolter at the University of Michigan rediscovered retinal neurodegeneration (DRN) as an important event in the course of DR, via studies of donor eyes of people with diabetes.15 He detected atrophy of ganglion cells (GCs) and degeneration of the inner nuclear layer (INL) in the donor eyes' retinas: (page 1138): "[…] since it is possible that the nerve damage is primary and a cause of the vascular changes […] The first change to occur in the retina in diabetes […], is the swelling and degeneration of retinal neurons […])." His work, which actually identified DR as a primary neuropathy, was later expanded by Barber and Gardner, initially at The Pennsylvania State University.16-18 Gardner later continued this work at the University of Michigan. Previously, in 1962 at Ohio State, Bloodworth described degeneration of the inner plexiform (IPL) and GCL in a histological study of 295 postmortem human eyes. He specifically identified pyknosis and fragmentation of GCL nuclei, features which are now recognized as typical characteristics of apoptosis.19 Interestingly, he described a lack of spatial correlation between GCL and vascular lesions.

Retinal neurodegeneration: functional and structural aspects

Early findings on DRN work led to a plethora of studies on neuroretinal pathophysiology in diabetes. We now know that diabetes induces neural apoptosis of ganglion, amacrine, and Müller cells, as well as increased expression of glial fibrillary acidic protein (GFAP) in Müller cells, activation of microglia17 (possibly caused by chronic glutamate toxicity,17, 20) inflammatory glial activation,21, 22 and increased expression of other neurotrophic factors, including basic fibroblast growth factor and ciliary neurotrophic factor.23 Altered glutamate metabolism have been noted recently in diabetic retinas.24, 25

These retinal abnormalities lead to functional changes, which have been well studied and typically precede clinical DR, in some cases occurring prior to the diagnosis of diabetes. Functional changes include deficits in the pattern electroretinogram (pattern ERG),26 increased implicit times in the multifocal ERG (mfERG),27-30 changes in oscillatory potentials,31 abnormal dark adaptation,32 abnormal contrast sensitivity,33, 34 abnormal color vision, and altered microperimetric and perimetric psychophysical testing.27, 35, 36 Typically, central visual acuity is not affected in early DR and is normal before the vascular lesions of clinical DR develop.37 We have demonstrated in a study, discussed more in detail below, that people with no or minimal DR have an average progressive neuroretinal (NFL, GCL, and IPL) thickness loss of 0.54 µm per year due to DRN.38 While seemingly small, to put this in perspective, in a large study of patients with glaucoma, the average decline in neuroretinal thickness between early (< 6 dB perimetric loss) and severe glaucoma (> 12dB loss) is 6 to 16µm.39 If DRN were to progress linearly at a rate of 0.54 µm per year over 10 years, it would result in a neuroretinal loss of 5.4µm, the same magnitude as severe glaucomatous damage. Of note, this would occur irrespective of the presence of microvascular DR. While patients with glaucoma receive treatment and regular perimetric examinations to anticipate and prevent visual loss,40 such studies are not employed routinely for people with diabetes.

In vivo quantification of structural changes due to DRN

Immunohistochemistry has identified structural changes indicative of neurodegeneration: a reduction in optic nerve axons and an increased number of glial cells.41 42 It goes without saying that these immunohistochemical structural findings have been made only in animal models or donor eyes. The recent development of Optical Coherence Tomography (OCT) and 3D quantification using image analysis of the neuroretina (NFL, GCL, and IPL) allow us to observe structural changes of diabetes in humans and in vivo, prior to the development of DR. At Iowa, we have developed image analysis algorithms that allow us to measure changes in retinal layer thickness of less than 0.25µm, substantially below the axial resolution of 5-8µm of clinical OCT devices.36, 37, 43 Our algorithms work on all commercially available OCT devices, and are publicly available for any researcher (available at www.iibi.uiowa.edu/content/shared-software-download). In a series of cross-sectional studies, these algorithms have allowed us to determine that the neuroretina (NFL, GCL, and IPL) are thinner in people with both type 1 and type 2 diabetes who have no or minimal, DR.44-48

Definition of clinical DR and retinal microvasculopathy

Once DR has started, its progression is predictable, leading to visual loss and blindness if undetected and untreated.49 Even though DR is typically divided into stages, (for example, according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) system3 or the International Clinical Diabetic Retinopathy (ICDR) severity scale,50) it is actually a continuum ultimately reflecting changes in gene expression. In the ensuing discussion, however, the following otherwise widely accepted definitions are used: the earliest clinical sign of DR is microaneurysms, in accordance with Friedenwald,2 and the earliest microscopic sign is pericyte loss, in accordance with Cogan.9 So-called 'preclinical DR' comprises additional vascular abnormalities such as acellular capillaries. 51-55

Relationship between diabetic retinal neurodegeneration and diabetic retinopathy

Early structural DRN, before the presence of DR, is associated with loss of visual function

Early neurodegeneration, even in the absence of clinical DR, is related to functional perimetric loss.35, 36, 56, 57 In a study of 32 people with type 1 diabetes and no or minimal DR,50 compared to 38 controls with no diabetes, we found that OCT analysis had a strong correlation of R = 0.65 between GCL thickness and Rarebit mean hit rate.58 This trend remained significant even after correction for DR status, diabetes duration, serum hemoglobin A1c (HbA1c), and age. Functional loss in diabetes before the occurrence of clinical DR has also been described using short wavelength automated perimetry (SWAP) and mfERG implicit times,27 contrast sensitivity and visual acuity,30, 33 abnormal dark adaptation,32 and frequency doubling perimetry.35 Prior to the development of DR, DRN affects the inner and middle retina, including bipolar cells, but not of the outer retina; we deduce this from the fact that mfERG implicit times are affected, but amplitude is not.59 OCT-based structural abnormalities of the inner and middle retinal layers have not yet been correlated with abnormalities on these other functional assessment.

DRN is not caused by the microvasculopathy of DR

We do know that the structural changes that occur in DRN precede clinical DR in people with diabetes and precede DR microvasculopathy in mouse models of diabetes. Specifically, we found that in 45 people with DM and no or minimal clinical DR there was a significant, progressive loss of NFL thickness (0.25μm/year) and GCL+IPL thickness (0.29μm/year) over a 4-year period.50 Of note, senescence alone results in minimal NFL and GCL+IPL thinning: only 0.1μm/year per layer.55 Interestingly, progressive retinal thinning in diabetes was primarily related to duration of disease and not to hemoglobin A1C (HbA1C). One hypothesis is that retinal neurovascular cells are more damaged by fluctuating glucose levels more so than by persistent hyperglycemia. 60 In 6 donor eyes of people with diabetes but no clinical DR, the NFL was significantly thinner on average (17.3μm) than in 6 control donor eyes (30.4μm) of similar age; however, retinal capillary density did not differ between the two groups.

Mouse models have successfully characterized the sequence of the events in DRN via OCT image analysis and immunohistochemistry, a feat that is exceptionally difficult in humans.38

In one study, OCT analysis demonstrated significant and progressive inner retinal thinning in streptozotocin-induced (STZ) "type 1" and B6.BKS(D)-Leprdb /J "type 2" diabetic mouse models. The "type 1" group had significant thinning of the NFL+GCL compared to the age-matched control group at both 6 and 20 weeks after induction of DM. This disparity increased over time: the "type 1" group had a relative a loss of 1.57μm (17.5%) at 6 weeks and 2.53μm (39.2%) at 20 weeks. In the "type 2" mouse group, we also found significant, progressive thinning of the NFL+GCL at 10 and 16 weeks of age compared to age- and strain-matched controls.

Comparatively, immunohistochemistry at 6 weeks showed no reduction in GCL density, as measured with anti-gamma-synuclein antibody (anti-SNCG) and nuclear 4',6-diamidino-2-phenylindole (DAPI) counterstain. However, in the "type 1" group, at 20 weeks, there was a significant GCL density loss. This finding mirrors immunohistochemistry findings in human donor eyes. GCL loss in "type 1" mice as early as 10 weeks has been demonstrated by others.61 In another study, both diabetic rats and human donor eyes demonstrated neural apoptosis as early as 4 weeks after diabetes onset; however, comparative analysis of simultaneous vascular changes was not performed in this study.16

In the STZ mice, at 6 weeks after DM induction, we found no difference between the density of endothelial-supporting retinal pericytes (p=0.72) or the percentage of acellular capillaries (p=0.22) in trypsin-digested retina. At 20 weeks, pericyte density was not statistically different in the NFL/GCL (p=0.063) or in the inner vascular plexus (p=0.30) and outer vascular plexus (p=0.18). At 20 weeks, we found no significant difference in retinal microvessel density (p=0.11), between STZ and controls.

In summary, in "type 1" and "type 2" mice neurodegeneration precedes microvascular change as measured by two independent methods (OCT analysis and immunohistochemistry). Specifically, there was no difference between the density of endothelial-supporting retinal pericytes, no difference in the number of acellular capillaries, no difference in pericyte density in the NFL/GCL and inner and outer vascular plexus. In concert, these findings confirm that there were no differences in the vasculature of the diabetic mice versus controls during the same time period while neural changes were readily identifiable.38

Finally, in a yet unpublished study, our group compared STZ-induced type 1 diabetes in wildtype mice against a vasculoprotected knockout mouse model. In this case, the vasculoprotective factor was inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2). While the vasculoprotected knockout mice did not develop all the characteristics of DR microvasculopathy, they demonstrated an equivalent amount of neurodegeneration as compared to wildtype mice. (This was quantified with both OCT analysis and immunohistochemistry). In addition, MRI analysis showed that total brain volume, as well as that of the hippocampus, caudate, and putamen, did not differ between wildtype and vasculoprotected mice. Combined, these aforementioned results support that DRN is progressive, is not prevented by vasculoprotection, and precedes vascular remodeling in diabetes.2, 9 Therefore, DRN is unlikely to be directly caused by the microvasculopathy of DR.

Implications for the retinal neurovascular unit

The Gardner group was the first to introduce the concept of the retinal neurovascular unit,18, 62 analogous to the cerebral neurovascular unit.63 The neurovascular unit was first hypothesized by Lewandowsky,64 and experimentally introduced by Hawkins et al, who demonstrated that it was the basis for the blood-brain barrier (BBB).63 The BBB was eventually confirmed to consist of the tight junctions between capillary endothelial cells.65 The retinal neurovascular unit lies adjacent to the retinal pigment epithelium (RPE), whose intercellular tight junctions form a blood-retina barrier analogous to the BBB. Characteristically, the retinal neurovascular unit has capillary beds in the GCL and INL. It includes astrocytes, Müller cells, amacrine neurons, and ganglion neurons, the last two of which are close to the microvasculature. Within the neurovascular unit, blood flow is regulated by local metabolites, including lactate, oxygen, and carbon dioxide. In 2007, Newman's group provided evidence of the potential mechanisms by which glial cells within rodent retinal tissue utilize signaling mechanisms to regulate blood vessel caliber.66 In diabetes, the neurodegenerative changes described above affect the retinal neurovascular unit as a whole.18 Although most existing literature on diabetic retinopathy implies that the vascular portion of the unit is the first to be damaged by excess glycosylation, the implication of our studies is that the earliest damage occurs within the neural portion of the unit.38

Neural dysfunction predicts the future location of clinical DR

In a series of studies, Bearse et al. found that local abnormalities in implicit time on multifocal ERG (mfERG) testing predicted local retinopathy 12 months later.28, 67, 68 Specifically, in 11 subjects with diabetes and non-proliferative DR, mfERG zones (a single mfERG hexagonal stimulus and its surrounding stimuli) that exhibited lengthened implicit times had a significant odds ratio of 31.4 for developing clinical DR within 12 months.28 In a second study of 41 subjects with diabetes and no clinical DR, zones that ultimately developed clinical DR could be predicted from a model factoring in mfERG implicit time plus six other non-ocular diabetic risk factors; the model had a sensitivity of 80% and specificity of 74%.68 In a follow-up study of 34 patients with DR and no macular edema, the development of central and temporal macular edema could be predicted with a model that included implicit time, ERG amplitudes, and two non-ocular risk factors, with a sensitivity of 84% and specificity of 76%.69 Functional changes in the middle and inner retina are therefore very unlikely to be caused by microvasculopathy. Lastly, in a longitudinal study of children and young adults with type 1 diabetes and no or minimal DR, and Humphrey Visual Field 24-2 at baseline, long-term follow-up showed that localized functional defects predicted future DR changes, also adding to the evidence that early functional neuropathy precedes DR microvasculopathy.70 Although Bearse et al. did not perform fluorescein angiography in their subjects – and as a result, could have failed to identify subclinical microvascular lesions – patients who were identified as having DR at the outset of the study met the definition of clinical DR: the presence of visible microaneurysms.2

Diabetic neuropathies outside the retina

Neurodegenerative complications of diabetes elsewhere in the body are widespread, and some have been experimentally confirmed as primary neurodegenerative processes. Corneal denervation, as measured by confocal microscopy,71 is related to peripheral neuropathy of the extremities.72, 73 Extensive studies have inversely correlated corneal nerve density with peripheral diabetic neuropathy (measured with an esthesiometer), as well as with diabetic limb amputations.73-76 The normal cornea does not contain blood vessels, ergo, corneal neuropathy is a primary neurodegeneration unrelated to microvasculopathy.

Cognitive dysfunction is also a complication of type 1 diabetes, manifesting as decreased motor processing speed and attentional function, while sparing learning and memory.61, 77-80 Many studies have established associations between diabetic cognitive dysfunction and progressive damage to brain structure, including increased cortical atrophy, microstructural abnormalities in white matter tracts, atrophy of the striatum (in type 1) and hippocampus (in type 2), and gray matter loss.81-85 At the moment, it is not clear how diabetes causes these structural losses in the brain, given that the brain and its microvasculature are not easily accessible in vivo.86, 87 The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) refuted the hypothesis that severe hypoglycemia caused cognitive dysfunction.79 Several studies have shown an association between structural changes from diabetes in the brain and retinal microvasculopathy.81, 88-91 Some authors therefore claim that the functional and structural changes in the brain induced by diabetes are primarily caused by microvasculopathy.78, 88, 90, 92, 93 Other authors, however, claim that neuropathy results directly from hyperglycemia 86 or from frequent oscillations in serum glucose levels,94 resulting in cognitive decline.

Cardiac autonomous neuropathy (CAN), the primary autonomic-type diabetic neuropathy, can lead to exercise intolerance, arrhythmias, cardiovascular events, orthostatic hypotension, and sudden death. 95 CAN has been associated with hyperglycemia, HbA1C level, and duration of diabetes. No microvascular links to CAN have been described.96

In summary, many diabetes complications are likely to be primary neuropathies, related to hyperglycemia, fluctuating serum glucose, and disease duration, while microvascular causes are either impossible (i.e., in corneal neuropathy) or unlikely (i.e., in CAN).

Conclusions

There is substantial, but exclusively circumstantial, evidence that DRN causes the microvascular changes of DR. After all, there are three possible relationships between DR microvasculopathy and DRN: i) microvasculopathy is a cause of neurodegeneration; ii) neurodegeneration is a cause of microvasculopathy or iii) they are mutually independent, i.e. DRN simply precedes DR without any effect on each other. Multiple studies have shown that DRN precedes DR microvasculopathy in humans and in mouse models of type 1 and type 2 diabetes, even in its earliest phenomenology of pericyte loss. Thus, i) is unlikely to be true. The mfERG studies by Bearse showed that functional DRN predicted microvasculopathy; thus, iii) is unlikely to be true. As such, ii) is the most likely relationship between DRN and DR: DRN is a cause of DR.

Currently, there is no direct evidence of ii), and so this relationship can only be arrived at by elimination of other possibilities. We require additional studies to clarify the temporal relationship between structural DRN and DR, as well as the mechanisms for delaying DRN. Delaying or halting the progression of DRN would, by default, need to slow progression of DR for a causative relationship to be established.

If DRN were confirmed as a cause of early DR, this would open a new avenue for prevention and treatment of DR: screening for DRN, currently absent, may precede or complement screening for DR. At present, the American Diabetes Association and the American Academy of Ophthalmology screening guidelines recommend that people with diabetes be screened for DR annually, while the Diabetic Retinopathy Preferred Practice Patterns recommends that they be treated if vision-threatening DR develops.97, 98 Early detection of DR can delay vision loss if treated with laser, anti-vascular endothelial growth factor agents, and/or steroids. 97, 99

Additional studies are needed to reveal the mechanism(s) of diabetes-induced neurodegeneration. In the future, neuroprotective treatments60, 100 that delay DRN and thereby delay early DR could potentially prevent vision loss and blindness secondary to diabetes. Economically, diabetes is poised to become an ever-increasing cause of vision loss and decreased productivity, due to an aging population. Neuroprotective treatments could result in a dramatic quality-of-life improvement for people with diabetes and their families. In tandem, they could lead to a significant economic benefit. We advocate that future clinical trials recognize the role of DRN as a i) primary driver of diabetic vision loss, and ii) as a marker for early retinal damage that could help identify patients who would benefit from neuroprotective treatments to prevent subsequent microvascular DR complications.

Acknowledgement

The authors wish to thank Patricia G. ('Trish') Duffel and Lucas T. Lenci, MD, for valuable assistance with the literature review.

Declaration of Conflicting Interests

MDA is named as inventor on patents and patent applications assigned to the University of Iowa. The methods referenced herein are based on these patents. SKL declares no conflicts of interest.

Funding

MDA is the Robert C. Watzke Professor of Ophthalmology and Visual Sciences. This work was partially supported by NIH grants R01 EY019112, R01 EY018853; the Department of Veterans Affairs: this material is the result of work supported with resources and the use of facilities at the Iowa City VAMC; contents are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Veterans Affairs, or the U.S. government; Research to Prevent Blindness, New York, NY; The authors wish to thank Drs. Elliott H. Sohn, Michael G. Anderson, James C. Folk, and Young H. Kwon, all at Iowa; Drs. Frank D. Verbraak and Hille W. van Dijk, both at Amsterdam; and Patricia G. Duffel, at Iowa for making this review possible.

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