Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus

Sohn, Elliott H.; Dijk, Hille W. van; Jiao, Chunhua; Kok, Pauline H. B.; Jeong, Woojin; Demirkaya, Nazli; Garmager, Allison; Wit, Ferdinand W. N. M.; Küçükevcilioğlu, Murat; Velthoven, Mirjam E. J. van; DeVries, J. Hans; Mullins, Robert F.; Kuehn, Markus H.; Schlingemann, Reinier O.; Sonka, Milan; Verbraak, Frank D.; Abràmoff, Michael D.

doi:10.1073/pnas.1522014113

Cited by 511 publications

(514 citation statements)

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“…9 Different studies using SDOCT have reported a decrease in RNFL and GCL/IPL thickness in diabetic patients without DR. [30][31][32] Sohn and associates quantified the decrease in the inner retinal layer thickness over time in 45 diabetic patients with or without mild nonproliferative DR and reported a progressive decrease in RNFL of 0.25 mm/year and in GCL/IPL of 0.29 mm/year over a period of 4 years, regardless of HbA1c, age, or sex. 33 Interestingly, in this study the variable retinopathy was negatively associated with the overall RT (central, S3, T3, I3, and N3 sectors), ONL (T6 and I6 sectors), and PR layer (N6 sector). In the span of just 1 year, the presence of DR decreased the overall RT in the studied locations between 13.04 and 16.63 mm.…”

Section: This Longitudinal Study Of 125 Type 2 Diabeticmentioning

confidence: 41%

Retina and Choroid of Diabetic Patients Without Observed Retinal Vascular Changes: A Longitudinal Study

Ferreira

Proença

Alves

et al. 2017

American Journal of Ophthalmology

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PURPOSE: To identify changes in choroidal thickness (CT) and all retinal layers of diabetic patients without diabetic retinopathy (DR) after 1 year of follow-up. DESIGN: Prospective observational cohort study. METHODS: Overall, 125 diabetic patients without DR were included. Two visits were scheduled: the first visit (V1) and a second visit after 12 months (V2). At both visits, patients received a complete ophthalmologic evaluation that included OCT. Each retinal layer thickness was calculated for 9 ETDRS sectors, and CT was measured at 13 locations. Generalized linear mixed-effects models were used.RESULTS: Of the 125 patients, 103 completed the study, and 9 of the 103 developed DR (8.7%). CT was significantly higher at V2 than at V1, with an average value of 10-17 mm at almost half the locations (500, 1000, and 1500 mm temporal; 500 and 1000 mm nasal; and 1000 mm superior to the fovea) (P < .001-.003). The thicknesses of the ganglion cell layer (I3 and N6 sectors), inner plexiform layer (S6 and N6 sectors), inner nuclear layer (T6 and N6 sectors), and outer plexiform layer (S6 sector), as well as the overall retinal thickness (RT) (S3, N3, I3, S6, and T6 sectors), were decreased at V2 (P < .001). Visible retinopathy was negatively associated with overall RT (central, S3, T3, I3, and N3 sectors, P [ .004-.024) and the thickness of the ONL (T6 and I6 sectors, P [ .007 and P [ .009) and photoreceptor layer (N6 sector, P [ .038). The presence of DR decreased the overall RT by 13.04-16.63 mm.CONCLUSIONS: Diabetic patients without DR showed a thicker choroid and a thinner retina, particularly in inner layers, after 1 year of follow-up. These structural changes may correspond to the early neurodegenerative phase of DR. ( 1 Of the 415 million diabetic patients worldwide in 2015, over one third will develop DR in their lifetime.2 The RETINODIAB study, an epidemiologic study that investigated the prevalence and progression rates of DR based on a national screening community program in Portugal, identified a 16.3% prevalence rate of DR and a 4.6% incidence rate of any DR within the first year in diabetic patients without retinopathy at baseline. 3,4

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Section: This Longitudinal Study Of 125 Type 2 Diabeticmentioning

confidence: 41%

Retina and Choroid of Diabetic Patients Without Observed Retinal Vascular Changes: A Longitudinal Study

Ferreira

Proença

Alves

et al. 2017

American Journal of Ophthalmology

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“…Photoreceptor degeneration in this condition promotes vasoregression. Given the role of the neurovascular unit in disease development and progression, it would be interesting to discover which comes first in the diabetic retina-vasoregression or neuronal degeneration [70]. Although most studies have suggested that vascular changes occur first, recent observations suggest the opposite.…”

Section: Models With Retinal Degeneration: Lessons For the Diabetic Rmentioning

confidence: 99%

Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond

2017

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Diabetic retinopathy remains a relevant clinical problem. In parallel with diagnostic and therapeutic improvements, the role of glycaemia and reactive metabolites causing cell stress and biochemical abnormalities as treatment targets needs continuous re-evaluation. Furthermore, the basic mechanisms of physiological angiogenesis, remodelling and pruning give important clues about the origins of vasoregression during the very early stages of diabetic retinopathy and can be modelled in animals. This review summarises evidence supporting a role for the neurovascular unit-composed of neuronal, glial and vascular cells-as a responder to the biochemical changes imposed by reactive metabolites and high glucose. Normoglycaemic animal models developing retinal degeneration, provide valuable information about common pathways downstream of progressive neuronal damage that induce vasoregression, as in diabetic models. These models can serve to assess novel treatments addressing the entire neurovascular unit for the benefit of early diabetic retinopathy. Diabetic retinopathy: the danger is not overThe overall prevalence of diabetic retinopathy is 35% among people with diabetes worldwide, with a current decline in both any retinopathy and sight-threatening stages [1]. Diabetic retinopathy ranks fifth among common causes for blindness or severe vision impairment and a recent meta-analysis revealed that the age-standardised prevalence of diabetic retinopathyrelated blindness will increase due to increasing populations and average age together with a reduction in death rates [2]. Lending support to the magnitude of the problem are reports that even when a person first presents at screening services, advanced diabetic retinopathy is present at levels that are no longer amenable to medical interventions [3,4]. Recent population-based studies from Europe revealed that screening-detected diabetic retinopathy appeared in more thanElectronic supplementary material The online version of this article (https://doi

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“…1998; Sohn et al. 2016), and apoptosis may be one of the mechanisms contributing to neuroretinal tissue loss in diabetes. Thereby, triggered retinal neurodegeneration may also participate in the development of early microvascular changes occurring in DR such as the breakdown of the blood–retina barrier, vasoregression and neurovascular coupling impairment (Simó & Hernández 2012).…”

Section: Discussionmentioning

confidence: 99%

“…2015; Sohn et al. 2016). Using optical coherence tomography (OCT), subtle atrophic changes in retinal thickness could be detected non‐invasively in diabetic patients with early retinopathy and to a lesser extent also in patients without retinopathy (Biallosterski et al.…”

Section: Introductionmentioning

confidence: 99%

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Correlation of retinal neurodegeneration with measures of peripheral autonomic neuropathy in type 1 diabetes

Pemp

Palkovits

Howorka

et al. 2018

Acta Ophthalmologica

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PurposeTo evaluate the relationship of neuroretinal layer thickness with sensitive measures of cardiovascular autonomic neuropathy in diabetic patients with non‐proliferative diabetic retinopathy (NPDR).MethodsTwenty‐seven eyes of 27 patients with type 1 diabetes presenting with mild‐to‐moderate NPDR were compared to 27 healthy control (HC) eyes matched for age and gender. The total macular volume (TMV) and the volumes of individual neurosensory layers in the macula were analysed from spectral domain optical coherence tomography using automated layer segmentation. Cardiovascular autonomic regulation was assessed by short‐term power spectrum analysis of heart rate variability (HRV) before, during and after an orthostatic challenge.ResultsThe patients had an age of 46 ± 12 years and diabetes since 28 ± 9 years. Diastolic and mean arterial pressure was lower in the patients compared to HCs. TMV (r = 0.58, p = 0.002), inner plexiform layer volume (IPLV; r = 0.39, p = 0.047) and inner nuclear layer volume (INLV; r = 0.60, p = 0.001) were associated with reduced recovery of low‐frequency (LF) spectral power of HRV after orthostatic load in diabetic patients but not in HCs. The response of LF spectral power during the orthostatic manoeuvre was blunted in patients compared to HCs (p = 0.02). Diabetes duration was negatively associated with TMV and INLV, whereas IPLV was significantly reduced in eyes with moderate NPDR compared to HCs.ConclusionThe results indicate a correlation between inner retinal tissue loss and diminished autonomic regulation in type 1 diabetic patients with mild‐to‐moderate NPDR. The observed changes can be interpreted as congruent early signs of retinal and systemic neuropathy in diabetes.

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Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus

Cited by 511 publications

References 57 publications

Retina and Choroid of Diabetic Patients Without Observed Retinal Vascular Changes: A Longitudinal Study

Retina and Choroid of Diabetic Patients Without Observed Retinal Vascular Changes: A Longitudinal Study

Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond

Correlation of retinal neurodegeneration with measures of peripheral autonomic neuropathy in type 1 diabetes

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